Comprehensive Dermatologic Drug Therapy [4th Edition] 9780323612548, 9780323612128

Table of contents :
Comprehensive Dermatologic Drug Therapy......Page 1
Copyright......Page 2
Dedication......Page 3
Contributors......Page 4
Preface......Page 11
Acknowledgments......Page 12
Introduction......Page 13
Distribution (The Drug has to Travel to the Site of Intended Action or to a Reservoir)......Page 14
Drug Receptors......Page 16
Signal Transduction and Transcription Factors......Page 18
Metabolism (The Drug Becomes More Hydrophilic to Favor Renal and Biliary Excretion)......Page 19
General Principles......Page 20
Summary......Page 22
Bibliography: Important Reviews and Chapters......Page 23
Introduction......Page 24
Patient Selection......Page 25
Baseline Laboratory and Related Tests......Page 26
Evolving Guidelines—Risk Factors......Page 27
Diagnosis......Page 28
Higher-Risk Scenarios......Page 29
Parting Thoughts......Page 31
Bibliography: Important Reviews and Chapters......Page 32
Introduction......Page 33
Cytochrome P-450 Enzyme System Overview......Page 34
CYP3A4 Variability......Page 35
CYP2C9 Polymorphism......Page 36
CYP2D6 Polymorphism......Page 37
Dihydropyrimidine Dehydrogenase......Page 38
P-Glycoprotein......Page 39
Thiopurine Methyltransferase......Page 40
Glucose-6-Phosphate Dehydrogenase......Page 41
Thymidylate Synthase and Other Polymorphisms in the Folate Pathway......Page 42
Pharmacogenomic Databases......Page 43
Conclusions and Future Directions......Page 44
References*......Page 45
Measures of Adherence......Page 48
Factors that Influence Adherence Behavior......Page 49
Choice of Treatments......Page 50
Stress Good Initial Adherence......Page 51
Achieving Adherence in Special Groups......Page 52
References*......Page 53
Principle #1. Not all patients with a given diagnosis are of equal risk for complications......Page 55
Medical Decision Making (Box 5.2)......Page 56
Principle #8. Master the causation algorithm to assess risk from drug therapy versus chance occurrence alone......Page 57
Principle #14. Seek an optimal level of certainty in medical decision making......Page 58
Principle #17. Gain ‘confidence’ in interpreting 95% confidence intervals for various ratios......Page 59
Principle #22. Suboptimal efficacy and treatment failure are different and must be distinguished......Page 60
Principle #25. Techniques to maximize the successful withdrawal of an intervention include (1) setting expectations, (2) accessi.........Page 61
Decision-Making Realities (Box 5.9)......Page 62
Introduction......Page 65
Phase I to IV Testing......Page 66
Off-Label Drug Use......Page 67
Regulation of Over-the-Counter Drugs, Biologics, and Generics......Page 68
Bibliography: Important Reviews......Page 69
Introduction......Page 70
References*......Page 77
Introduction......Page 80
Product Label ‘Lifecycle’ Changes......Page 81
General Principles Concerning Drug Withdrawal Decisions......Page 82
Bibliography: Important Reviews and Websites For Supplemental Information......Page 84
References......Page 85
9 - Systemic Antibacterial Agents......Page 86
Penicillins......Page 87
Cephalosporins......Page 92
Other Systemic Antibacterials that Inhibit Cell Wall Synthesis......Page 94
Macrolides......Page 95
Fluoroquinolones......Page 98
Tetracyclines......Page 99
Rifampin and Other Rifamycins......Page 106
Folate Synthesis Inhibitors......Page 110
Lincosamides......Page 112
Special Topics......Page 113
References*......Page 114
10 - Systemic Antifungal Agents......Page 129
Introduction......Page 130
Pharmacokinetics in Hair......Page 132
Mechanism of Action......Page 133
Clinical Use......Page 134
Contraindications......Page 138
Adverse Effects......Page 140
Monitoring Guidelines......Page 141
References*......Page 143
11 - Systemic Antiviral Agents......Page 148
Herpes Simplex Virus Infections. ACV can be administered topically, orally, and intravenously. The oral form is the most widely .........Page 149
Off-Label Dermatologic Uses......Page 152
Herpes Simplex Infections. VACV is indicated for the treatment of both genital and orofacial HSV infections. For first-episode g.........Page 153
Other Herpes Simplex Infections. A variety of subsets of HSV can be treated with VACV in a fashion similar to the regimens outli.........Page 154
Herpes Zoster. FCV has been shown to be highly effective in the treatment of HZ. The FDA-recommended FCV dose for zoster in immu.........Page 155
Varicella-Zoster Virus Vaccines. The first available vaccine for prevention of a VZV virus infection is a live-attenuated vaccin.........Page 156
Overview......Page 157
Summary......Page 158
Ivermectin......Page 163
Clinical Use......Page 164
Pharmacology......Page 165
Pharmacology......Page 166
Alternative Agents—Doxycycline As Antiparasitic Agent......Page 167
Bibliography: Important Reviews and Chapters......Page 168
References*......Page 169
13 - Systemic Corticosteroids......Page 172
Structure......Page 173
Metabolism and Excretion......Page 174
Mechanism of Action......Page 175
Food and Drug Administation-Approved Indications and Off-Label Dermatologic Uses......Page 178
Intramuscular Corticosteroid Administration......Page 180
Adverse Effects......Page 181
Hypothalamic-Pituitary-Adrenal-Axis Suppression......Page 187
Therapeutic Guidelines......Page 190
References*......Page 194
Introduction......Page 199
Metabolism and Excretion......Page 200
Folic Acid Effects on Methotrexate Therapy. Q14.3 The use of folic acid as a method of inhibiting MTX-induced GI AE and reducing.........Page 202
Psoriasis. The major clinical use of MTX in dermatology is in the therapy of psoriasis.24 The selection of the patient for the i.........Page 203
Immunobullous Dermatoses. Diseases of presumed immunologic origin may also respond to MTX. Specifically, bullous diseases, such .........Page 204
Hepatotoxicity. The potential for hepatotoxicity in a patient treated with long-term MTX is an important consideration.24,90 Hep.........Page 205
Hematologic Effects. Hematologic toxicity, such as pancytopenia, presents the greatest potential for loss of life as a result of.........Page 206
General Issues and Risk-Factor Assessment. Before the first dose, a thorough evaluation of the patient should be completed. The .........Page 208
Q14.11 There are several other instances in which a pretreatment MTX liver biopsy is necessary, although subsequent point 5 is i.........Page 209
Therapeutic Guidelines......Page 210
Introduction......Page 217
Metabolism and Excretion......Page 218
Off-Label Dermatologic uses......Page 220
Adverse Effects (Box 15.3)......Page 221
Summary......Page 224
References*......Page 225
Introduction......Page 229
Clinical Use......Page 230
Psoriasis......Page 231
Lupus Erythematosus......Page 232
Carcinogenicity......Page 233
Gastrointestinal Toxicity......Page 234
Pregnancy......Page 235
Monitoring Guidelines......Page 236
References*......Page 237
Introduction......Page 242
Pharmacology......Page 243
Clinical Use......Page 245
Monitoring Guidelines......Page 248
Summary......Page 252
References*......Page 253
Introduction......Page 257
Phosphodiesterase 4 Inhibitor Therapy......Page 258
Clinical Use......Page 259
Clinical Use......Page 260
Additional Off-Label Uses......Page 261
Monitoring......Page 264
Bibliography: Important Reviews and Chapters......Page 265
References*......Page 266
Introduction......Page 270
Pharmacology (Table 19.2)......Page 272
Clinical Use......Page 273
Clinical Use......Page 274
Pharmacology......Page 275
Adverse Effects......Page 276
Chlorambucil......Page 279
Off-Label Dermatologic Uses......Page 280
Melphalan......Page 281
References*......Page 282
Introduction......Page 288
Absorption and Bioavailability......Page 289
Excretion......Page 290
Mechanisms of Action (Table 20.3)......Page 291
Dermatologic Indications – Consistent Efficacy......Page 292
Adverse Effects—Pharmacologic......Page 294
Adverse Effects—Idiosyncratic......Page 295
Monitoring Guidelines......Page 297
References*......Page 299
Web References......Page 300
Introduction......Page 304
Absorption and Bioavailability......Page 305
Clinical Use......Page 306
Off-Label Uses......Page 308
Adverse Effects......Page 309
Monitoring Guidelines84–86,125......Page 311
Treatment of PCT......Page 312
Bibliography: Important Reviews and Chapters......Page 313
References*......Page 314
Introduction and Historical Perspective......Page 319
Structure......Page 321
Mechanism At the Nuclear Level. Retinoids exert their physiologic effects by binding to receptors present in the nucleus (Table .........Page 322
Practical Considerations......Page 323
Acne Vulgaris. The only systemic retinoid that is FDA approved for the treatment of acne is isotretinoin. Current FDA guidelines.........Page 324
Chemoprevention of Malignancy. Q22.6 Given the ability of retinoids to influence epidermal development and differentiation,87 va.........Page 325
Teratogenicity—Women Exposed To Retinoids. Teratogenicity is the most important AE of the retinoids. Q22.7 Common retinoid-induc.........Page 326
The ‘iPledge’ Registry Requirements. Because of concerns about the number of pregnancies that continued to occur, while patients.........Page 328
Lipid Effects. Q22.8 The most common laboratory abnormality observed in patients taking systemic retinoids is elevation in serum.........Page 329
Bone Effects. The potential for retinoid use to cause similar bone effects to what is seen in chronic vitamin A toxicity (diffus.........Page 330
Hematologic Effects. In CTCL studies, up to 43% of patients receiving bexarotene (300 mg/m2 daily) had reversible leukopenia (10.........Page 331
Therapeutic Guidelines......Page 332
23 - Psoralen Plus Ultraviolet A Photochemotherapy and Other Phototherapy Modalities......Page 341
Clinical Use......Page 342
Treatment Procedure......Page 343
Treatment Protocol......Page 345
Introduction......Page 346
Clinical Use......Page 347
References*......Page 348
Introduction......Page 355
Treatment Delivery and Considerations......Page 356
Autoimmune Dermatoses......Page 357
US Food and Drug Administration-Approved Indications......Page 358
Other Dermatologic Uses—Treatment of T-Cell-Mediated Autoimmune Dermatoses......Page 360
Adverse Effects......Page 362
References*......Page 363
Absorption and Bioavailability......Page 368
Mechanisms of Action......Page 369
Formulations Available......Page 370
US Food and Drug Administration-Approved Indications......Page 371
Off-Label Uses......Page 372
General Therapeutic Guidelines for Photodynamic Therapy Treatment of Actinic Keratoses......Page 373
References*......Page 374
Introduction—Psoriasis Pathogenesis......Page 377
Clinical Use......Page 380
Off-Label Dermatologic Uses......Page 383
Clinical Use......Page 385
Clinical Use......Page 387
Adverse Effects of the TNFi In General......Page 388
Bibliography: Important Reviews and Chapters......Page 390
References*......Page 391
Monoclonal Antibody Treatments......Page 399
Ustekinumab......Page 402
Clinical Use—Ustekinumab......Page 405
Adverse Effects......Page 406
Overview of Adverse Effects—Interleukin Inhibitors......Page 407
References*......Page 408
Introduction......Page 411
Dermatologic Indications and Dosages......Page 412
Clinical Use: Plaque Psoriasis......Page 413
Safety and Monitoring......Page 414
Clinical Use: Plaque Psoriasis......Page 415
Clinical Use: Plaque Psoriasis......Page 416
Candidiasis......Page 417
Summary......Page 418
References*......Page 419
Introduction......Page 422
Clinical Use......Page 423
Pharmacology......Page 425
Clinical Use......Page 426
Clinical Use......Page 427
Adverse Effects......Page 428
Bibliography: Important Reviews and Chapters......Page 429
References*......Page 430
30 - Rituximab......Page 433
Pharmacology......Page 434
Clinical Use......Page 436
Bibliography: Important Reviews and Chapters......Page 440
References*......Page 441
Dupilumab......Page 445
Mechanism of Action. Q31.4 Dupilumab directly antagonizes the α-subunit of both type 1 and type 2 IL-4 receptors. Type 1 recepto.........Page 446
Special Populations. Dupilumab has not been studied in human pregnancy. Endogenous IgG transfers from mother to fetus across the.........Page 447
Pharmacokinetics. The pharmacokinetics of omalizumab follow a first-order absorption model and become linear with dosages greate.........Page 448
US Food and Drug Administration-Approved Indications (Box 31.3). Omalizumab is FDA-approved for patients 6 years and older with .........Page 449
Anaphylaxis. Q31.10 Omalizumab carries a Boxed Warning for the risk of anaphylaxis. Symptoms of anaphylaxis with omalizumab incl.........Page 450
Other Biologic Therapies in Development......Page 451
Second-Generation H1 Antihistamines......Page 459
Antihistamine Mechanism of Action......Page 460
First-Generation Antihistamines......Page 461
Second-Generation H1 Antihistamines......Page 462
Levocetirizine......Page 464
H2 Antihistamines......Page 465
Oral and Topical Doxepin......Page 466
References*......Page 467
33 - Vasoactive and Antiplatelet Agents......Page 470
Clinical Use......Page 471
Pharmacology......Page 473
Pharmacology......Page 474
Clinical Use......Page 475
Phosphodiesterase-5 Inhibitors......Page 476
References*......Page 477
34 - Antiandrogens and Androgen Inhibitors......Page 481
Mechanism of Action......Page 482
Pharmacology......Page 484
Clinical Use......Page 486
Progestins......Page 488
Experimental Therapies......Page 490
Clinical Use......Page 491
Adverse Effects......Page 492
Off-Label Use......Page 493
Pharmacology......Page 494
Adverse Effects......Page 495
References*......Page 496
Web References......Page 497
Introduction......Page 502
General Principles in Management of the Above Categories......Page 503
General Principles......Page 504
General Principles......Page 505
Specific Medications......Page 506
Alternatives to Selective Serotonin Reuptake Inhibitor Antidepressants......Page 510
General Principles......Page 511
Specific Medications—Pimozide......Page 512
General Principles......Page 514
Summary......Page 515
References*......Page 516
Introduction......Page 519
Clinical Use......Page 520
References*......Page 526
37 - Systemic Anticancer Agents: Dermatologic Indications and Adverse Events......Page 532
Epidermal Growth Factor Receptor Inhibitors......Page 533
Sorafenib......Page 536
Nilotinib......Page 540
Paclitaxel......Page 541
Denileukin Diftitox......Page 542
Pralatrexate......Page 543
Nivolumab......Page 544
References*......Page 545
38 - Hedgehog Pathway Inhibitors......Page 549
Absorption and Distribution......Page 550
Us Food and Drug Aministration-Approved Indications......Page 551
Systemic Sclerosis......Page 553
Overview of Other Adverse Effects......Page 554
Treatment Resistance......Page 556
Other Hedgehog Inhibitors......Page 557
References*......Page 558
Introduction......Page 562
Pharmacology......Page 563
Clinical Use......Page 564
Adverse Effects......Page 566
Lipoprotein Physiology and Pathophysiology......Page 569
Pharmacology......Page 570
Clinical Use......Page 571
Pharmacology......Page 572
Clinical Use......Page 573
Adverse Effects......Page 574
Ezetimibe......Page 575
References*......Page 576
40 - Miscellaneous Systemic Drugs......Page 580
Anticholinergic Agents—Glycopyrrolate and Oxybutynin......Page 581
Biotin......Page 582
Pharmacology......Page 583
Off-Label Dermatologic Uses......Page 584
Off-Label Dermatologic Uses......Page 585
Pharmacology......Page 587
Clinical Use......Page 588
Clinical Use......Page 589
Pharmacology......Page 590
Clinical Use......Page 591
Thalidomide......Page 592
Pharmacology......Page 593
Off-Label Dermatologic Uses—Well-Documented Benefits......Page 594
Adverse Effects......Page 595
Monitoring Guidelines......Page 596
Gabapentin and Pregabalin......Page 597
Bibliography: Important Reviews and Chapters......Page 598
References*......Page 599
Introduction......Page 606
Clinical Use......Page 607
Pharmacology......Page 609
Pharmacology......Page 610
Pharmacology......Page 611
Silver Sulfadiazine......Page 612
Clinical Use......Page 613
Pharmacology......Page 615
Pharmacology......Page 616
Clinical Use......Page 617
Pharmacology......Page 618
Triclosan......Page 619
References*......Page 620
Introduction......Page 630
Azoles......Page 631
Clinical Use......Page 633
Pharmacology......Page 634
Clinical Use......Page 635
Clinical Use......Page 636
Clinical Use......Page 637
Dermatophytes......Page 638
Candidiasis......Page 639
Special Properties......Page 640
References*......Page 641
43 - Topical and Intralesional Antiviral Agents......Page 648
Clinical Use......Page 649
Clinical Use......Page 651
Idoxuridine......Page 652
Mechanism of Action......Page 653
Clinical Use......Page 654
Podophyllin and Podofilox......Page 655
Clinical Use......Page 656
Mechanism of Action......Page 657
References*......Page 658
Pharmacology......Page 663
Pharmacology......Page 665
Clinical Comparisons. Q44.6 Numerous studies have proven that malathion has superior pediculicidal and ovicidal activity compare.........Page 666
Melaleuca Alternifolia (Tea Tree) Oil......Page 667
References*......Page 668
Introduction......Page 671
Pharmacokinetics......Page 672
Mechanism of Action......Page 674
Indications......Page 676
Adverse Effects—Systemic......Page 679
Adverse Effects—Local......Page 680
Therapeutic Guidelines......Page 682
References*......Page 687
46 - Topical Retinoids......Page 694
Teratogenicity......Page 695
All-Trans Retinol and All-Trans Retinoic Acid......Page 698
Tazarotene......Page 700
Bexarotene......Page 701
Indications......Page 702
Adverse Effects......Page 705
References*......Page 706
5-Fluorouracil......Page 711
Pharmacology......Page 712
Clinical Use......Page 713
Clinical Use......Page 714
Therapeutic Guidelines......Page 715
Pharmacology......Page 716
Clinical Use......Page 717
References*......Page 718
Tacrolimus......Page 721
Clinical Use......Page 722
Clinical Use......Page 726
References*......Page 728
Introduction......Page 734
Metabolism......Page 735
Calcipotriene......Page 736
Plaque Psoriasis. Calcipotriene is approved for the treatment of plaque-type psoriasis in adults. Early studies were all short t.........Page 737
Scalp Psoriasis. A scalp formulation of calcipotriene–betamethasone dipropionate developed for once-daily treatment of scalp pso.........Page 738
Vitiligo. A placebo-controlled, double-blind study assessing whether the addition of topical calcipotriene to psoralen plus UVA .........Page 739
References*......Page 740
Introduction......Page 744
Ultraviolet B Sunscreens......Page 745
Ultraviolet A Sunscreens......Page 746
Physical Blockers......Page 747
Indications......Page 748
Sun Protection Factor Level......Page 749
Sunscreen Vehicles......Page 750
Adverse Effects......Page 751
Special Patient Group Instructions......Page 752
Sunless Tanners—Dihydroxyacetone......Page 753
References*......Page 754
Dermatoses Involving the Scalp......Page 757
Mechanism of Action......Page 759
Clinical Use......Page 760
Adverse Effects......Page 762
Management Strategy......Page 763
References*......Page 765
Web References......Page 766
Structure......Page 770
Mechanism of Action......Page 771
Xerosis and Ichthyosis......Page 772
Psoriasis......Page 773
Formulations and Bioavailability......Page 774
Summary......Page 775
References*......Page 776
Superficial Chemical Peels......Page 779
Medium-Depth Chemical Peels......Page 780
Clinical Use......Page 781
References*......Page 783
54 - Products for the Care of Chronic Wounds......Page 785
Physical Examination......Page 786
Laboratory Evaluation......Page 788
Compression Therapy for Venous Leg Ulcers......Page 789
Wound Bed Preparation......Page 790
References*......Page 793
Introduction......Page 797
Clinical Use......Page 798
Adverse Effects......Page 800
Mechanism of Action......Page 801
Pharmacology......Page 802
Adverse Effects......Page 803
Dermatologic Uses......Page 804
References*......Page 805
Contact Dermatitis: the Concept......Page 811
Regional Approach......Page 812
Acknowledgment......Page 816
References*......Page 817
Pharmacology......Page 819
Clinical Use......Page 820
Pharmacology......Page 821
Pharmacology......Page 822
Pharmacology......Page 823
Pharmacology......Page 824
References*......Page 825
58 - Local Anesthetics......Page 829
Pharmacology......Page 830
Clinical Use......Page 832
Off-Label Dermatologic Uses......Page 835
Therapeu\tic Guidelines......Page 838
Clinical Use......Page 839
Off-label Dermatologic Uses......Page 840
Dyclonine......Page 841
Adverse Effects......Page 842
Drug Interactions......Page 844
Clinical Use......Page 845
Bibliography: Important Reviews and Chapters......Page 846
References*......Page 847
Collagen......Page 854
Poly-L-Lactic Acid......Page 855
Immediate Adverse Effects (0–2 Days)......Page 857
Late Adverse Effects (15 Days–1 Year)......Page 858
References*......Page 859
Introduction and History......Page 861
Mechanism of Action......Page 862
Indications......Page 865
Adverse Effects......Page 866
Therapeutic Guidelines......Page 867
References*......Page 869
Introduction......Page 872
Erosive Gingivostomatitis......Page 873
Steroid-Sparing Immunosuppressants......Page 874
Topical Therapy......Page 875
Hairy Tongue......Page 876
Anti-inflammatory Agents......Page 877
Mucositis (Stomatitis)......Page 878
Systemic Therapy......Page 879
Xerostomia......Page 880
Burning Mouth Syndrome......Page 881
Systemic Therapy. Q61.11......Page 882
62 - Hepatotoxicity of Dermatologic Drug Therapy......Page 886
Hepatic Drug Metabolism......Page 887
Polymorphisms......Page 888
General Mechanisms Involved......Page 889
General Risk Factors......Page 890
Drug Information Dissemination Issues......Page 891
Classification Systems......Page 892
Less Common Drug Etiologies......Page 893
Referral Criteria......Page 894
Background Issues......Page 895
Looking to the Future—Lessons from the Past......Page 896
References*......Page 897
Introduction......Page 900
Prediction of Risk for Hematologic Toxicities......Page 901
Aplastic Anemia (Pancytopenia)......Page 902
Neoplasia......Page 903
Azathioprine......Page 904
Hydroxyurea......Page 905
Sulfasalazine......Page 906
Colchicine......Page 907
Miscellaneous Drugs......Page 908
Management of Agranulocytosis......Page 909
References*......Page 910
Introduction......Page 915
General Principles and a Drug Causation Determination Algorithm......Page 916
Entire Population Versus Disease-Specific Databases......Page 917
Malignancies Having Increased Risk with Organ Transplantation......Page 918
Viral Cofactors......Page 919
Alkylating Agents—Cyclophosphamide and Chlorambucil......Page 920
Biologic Therapies for Psoriasis—Tumor Necrosis Factor Inhibitors......Page 921
Biologic Therapies and Cyclosporine......Page 922
References*......Page 923
65 - Dermatologic Drugs During Pregnancy and Lactation......Page 927
Timing—First Trimester......Page 928
Timing—Second Trimester......Page 929
Guide for Specific Drug Use......Page 931
References*......Page 941
Web References......Page 942
Introduction......Page 946
Absorption......Page 947
P-Glycoprotein (Fig. 66.2)......Page 949
Metabolism......Page 950
Cytochrome P-450 Enzymes Background Information......Page 951
Induction of Cytochrome P-450 3A4......Page 954
Inhibition of CYP3A4......Page 955
Drug Interaction Risks by Drug Category......Page 957
Azole Antifungals......Page 958
Grapefruit Juice......Page 959
HMG CoA Reductase Inhibitors......Page 960
Warfarin......Page 961
Do All Drugs in a Given Class Behave in a Similar Manner?......Page 962
References*......Page 963
Introduction......Page 967
Pseudolymphoma......Page 968
Q67.2 DRESS has been commonly associated with the aromatic anticonvulsants, namely phenytoin, phenobarbital, oxcarbazepine, and .........Page 969
Minocycline......Page 970
Treatment......Page 971
Drug-Induced Lupus......Page 972
Antitumor Necrosis Factor Agents......Page 973
General Discussion......Page 975
Introduction......Page 981
Basic Legal Principles......Page 982
Systemic Drugs and Informed Consent......Page 983
Medicolegal Risk Management......Page 984
Dermatology Malpractice......Page 985
References*......Page 986
Web References......Page 987
Introduction......Page 988
The Patient......Page 989
Clinical Evidence......Page 990
Feasibility......Page 991
Evaluation of the Treatment......Page 993
Summary......Page 994
References*......Page 995
Introduction......Page 997
Pediatric Pearls......Page 998
Topical Corticosteroids......Page 999
Systemic Corticosteroids......Page 1001
Beta Blockers......Page 1002
Methotrexate......Page 1003
Cyclosporine......Page 1004
Infliximab......Page 1005
References*......Page 1006
Section 1—Pharmacology Basic Science......Page 1010
Section 2—Clinical Use......Page 1011
Section 3—Severe Adverse Effects......Page 1013
Section 5 - Drug Safety Monitoring......Page 1015
Section 7—Miscellaneous Issues......Page 1016
General Principles for Creating This Appendix......Page 1017
A......Page 1019
B......Page 1024
C......Page 1025
D......Page 1029
E......Page 1032
F......Page 1033
G......Page 1034
H......Page 1035
I......Page 1037
L......Page 1039
M......Page 1041
N......Page 1043
O......Page 1044
P......Page 1045
R......Page 1049
S......Page 1051
T......Page 1053
V......Page 1056
Z......Page 1057

Citation preview

Comprehensive Dermatologic Drug Therapy FOURTH EDITION

Stephen E. Wolverton, MD Theodore Arlook Professor of Clinical Dermatology Department of Dermatology Indiana University School of Medicine Indianapolis, Indiana, USA

Associate Editor

Jashin J. Wu, MD Founder and Course Director San Diego Dermatology Symposium May 29-31, 2020; Founder and CEO Dermatology Research and Education Foundation Irvine, California, USA

Elsevier 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

COMPREHENSIVE DERMATOLOGIC DRUG THERAPY, FOURTH EDITION Copyright © 2021 by Elsevier, Inc. All rights reserved.

ISBN: 978-0-323-61211-1

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Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors, or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

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This book is dedicated to the following individuals: To my wife Cheryl, for her support and help over the past 18 months of the book development and the editorial process, let alone for our 39 years of marriage. To our sons Dr. Jay Edward Wolverton (age 33) and Justin David Wolverton (age 31), who continue to enable us to see the world through their creative minds, kind hearts, and strong relationships. To my parents Elizabeth Ann (1924–2000) and Dr. George M. Wolverton Sr. (1925–2011), for the passion, wisdom, compassion, and encouragement provided throughout their lives; these traits continue to have a positive influence on my life on a daily basis. And lastly to my wonderful (and large) nuclear family with three sisters (Anne, Cynthia, and Pam) and five brothers (George Jr. [1951–1996], Greg, Jeff, Doug, and Dan), for their kindness to and consideration for others, and their ongoing camaraderie and generosity. Stephen E. Wolverton, MD To my loving wife Stephanie, who lovingly supports my career over 10 years of marriage. To my baby boy Conrad, who I hope grows to be a man of maturity, wisdom, intellect, and strength. To my parents Shin Wu, MD and Jane Joaquin-Wu, MD, who installed in me the value of hard work and perseverance: thank you for all that you have given me. Jashin J. Wu, MD

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Contributors

David R. Adams, MD, PharmD Professor of Dermatology Department of Dermatology Penn State Hershey Medical Center Hershey, Pennsylvania, USA

Jonathan A. Braue, MD Staff Dermatologist Cleveland Clinic Indian River Hospital Scully-Welsh Cancer Center Vero Beach, Florida, USA

Stewart Adams, MD, FRCP, FAAD Clinical Lecturer Department of Medicine University of Calgary Calgary, Alberta, Canada

Robert T. Brodell, MD Professor and Chair Department of Dermatology University of Mississippi Medical Center Jackson, Mississippi, USA; Instructor Department of Dermatology University of Rochester School of Medicine and Dentistry Rochester, New York, USA; Professor Department of Pathology University of Mississippi Medical Center Jackson, Mississippi, USA

Mina Amin, MD Department of Dermatology Kaiser Permanente Los Angeles Medical Center Los Angeles, California, USA Nidhi Avashia-Khemka, MD Assistant Professor of Clinical Dermatology Department of Dermatology Indiana University School of Medicine Indianapolis, Indiana, USA Kristen M. Beck, MD Clinical Fellow Psoriasis and Skin Treatment Center University of California San Francisco, California, USA Bhavnit K. Bhatia, MD Physician Department of Dermatology The Permanente Medical Group Richmond, California, USA Sravya Mallam Bhatia, MD Resident Physician Department of Dermatology Duke University Medical Center Durham, North Carolina, USA Tina Bhutani, MD Assistant Professor Psoriasis and Skin Treatment Center University of California San Francisco, California, USA

vi

David G. Brodland, MD Assistant Professor Department of Dermatology, Assistant Professor Department of Otolaryngology, Assistant Professor Department of Plastic Surgery University of Pittsburgh Pittsburgh, Pennsylvania, USA Candace Broussard-Steinberg, MD, BS Resident Department of Dermatology Indiana University School of Medicine Indianapolis, Indiana, USA Jeffrey P. Callen, MD, FACP, MAAD, MACR Professor of Medicine (Dermatology) Chief Division of Dermatology University of Louisville School of Medicine Louisville, Kentucky, USA

Contributors

Charles Camisa, MD, FAAD Director and Founder Psoriasis Treatment Center Riverchase Dermatology Naples, Florida, USA; Affiliate Associate Professor Department of Dermatology and Cutaneous Surgery University of South Florida Tampa, Florida, USA Ahmad Chehade, PharmD Clinical Pharmacist Calgary, Alberta, Canada Margot Chima, MC Resident Department of Dermatology Icahn School of Medicine at Mount Sinai New York, New York, USA Richard A. Clark, MD Professor Department of Biomedical Engineering and Dermatology Stony Brook University Stony Brook, New York, USA Abigail Cline, MD, PhD Resident Physician Department of Dermatology Metropolitan Hospital New York, New York, USA Kelly M. Cordoro, MD Professor of Dermatology and Pediatrics University of California San Francisco, California, USA Julio C. Cruz Ramón, MD Dermatologist and Dermatopathologist Buckeye Dermatology Dublin, Ohio, USA Loretta S. Davis, MD Professor and Chair Department of Dermatology, Residency Program Director Medical College of Georgia Augusta University Augusta, Georgia, USA Salma de la Feld, MD Assistant Professor Department of Dermatology Emory University Augusta, Georgia, USA

Cynthia M.C. DeKlotz, MD, MASt Assistant Professor of Clinical Medicine and Pediatrics Internal Medicine and Pediatrics Division of Dermatology Georgetown University School of Medicine; Pediatric and Adult Dermatologist Department of Dermatology MedStar Washington Hospital Center/Georgetown University Hospital Washington, District of Columbia, USA Gabrielle-Eugenie Duprat, MD Indiana University School of Medicine Indianapolis, Indiana, USA William H. Eaglstein, MD Professor and Chairman Emeritus The Doctor Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami, Florida, USA Carly A. Elston, MD Assistant Professor Department of Dermatology University of Alabama at Birmingham Birmingham, Alabama, USA Dirk M. Elston, MD Professor and Chair Department of Dermatology Medical University of South Carolina Charleston, South Carolina, USA Ashley N. Emerson, MD Assistant Professor Department of Dermatology University of Mississippi Medical Center Jackson, Mississippi, USA Stephanie K. Fabbro, MD Attending Dermatologist Department of Dermatology Buckeye Dermatology Columbus, Ohio, USA Steven R. Feldman, MD, PhD Professor Department of Dermatology Wake Forest School of Medicine Winston-Salem, North Carolina, USA Laura K. Ferris, MD, PhD Associate Professor of Dermatology University of Pittsburgh Pittsburgh, Pennsylvania, USA Kelly A. Foley, PhD Medical Research Associate Department of Dermatology Mediprobe Research Inc. London, Ontario, Canada

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viii

Contributors

Seth B. Forman, MD Dermatologist Dermatology Department of ForCare Medical Group Tampa, Florida, USA Craig Garofola, DO PGY4 Dermatology Resident Virginia College of Osteopathic Medicine/Lewis Gale Montgomery Blacksburg, Virginia, USA Jeffrey R. Gehlhausen, MD, PhD Resident Physician Department of Dermatology Yale New Haven Hospital New Haven, Connecticut, USA Joel M. Gelfand, MD, MSCE Professor of Dermatology and Epidemiology Departments of Dermatology and Biostatisitcs, Epidemiology and Informatics University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania, USA Michael Girardi, MD Professor, Vice Chair, and Residency Program Director Department of Dermatology Yale School of Medicine New Haven, Connecticut, USA Tobias Goerge, MD Professor of Dermatology Department of Dermatology University of Münster Münster, Germany Kenneth B. Gordon, MD Professor and Chair Department of Dermatology Medical College of Wisconsin Milwaukee, Wisconsin, USA Teri M. Greiling, MD, PhD Assistant Professor Department of Dermatology Oregon Health and Science University Portland, Oregon, USA Erin E. Grinich, MD Resident Physician Department of Internal Medicine Loma Linda University Medical Center Loma Linda, California, USA Daniel Grove, MD Resident Department of Dermatology Indiana University Indianapolis, Indiana, USA

Aditya K. Gupta, MD, PhD, FRCP(C) Professor Division of Dermatology, Department of Medicine University of Toronto Toronto, Ontario, Canada; Director Mediprobe Research Inc. London, Ontario, Canada Anita Haggstrom, MD Associate Professor Department of Dermatology Indiana University Indianapolis, Indiana, USA Christopher T. Haley, MD Clinical Research Fellow Department of Dermatology Center for Clinical Studies Webster, Texas, USA Russell P. Hall III, MD J. Lamar Callaway Professor and Chair Department of Dermatology Duke University Medical Center Durham, North Carolina, USA Iltefat Hamzavi, MD, FAAD Senior Staff Physician Department of Dermatology Henry Ford Health System; Clinical Associate Professor Wayne State University SOM Detroit, Michigan, USA Michael P. Heffernan, MD US Dermatology Lead Department of Dermatology Probity Medical Research San Luis Obispo, California, USA Yolanda R. Helfrich, MD Associate Professor Department of Dermatology University of Michigan Medical School Ann Arbor, Michigan, USA Adam B. Hessel, MD Adjunct Assistant Professor Department of Dermatology The Ohio State University Columbus, Ohio, USA; Dermatologist and Dermatopathologist Buckeye Dermatology Dublin, Ohio, USA Shauna Higgins, MD Clinical Research Fellow Department of Dermatology University of Nebraska Medical Center Omaha, Nebraska, USA

Contributors

Whitney A. High, MD, JD, MEng Professor and Vice Chairman Departments of Dermatology and Pathology University of Colorado Denver, Colorado, USA

Hee Jin Kim, MD Dermatology Resident Department of Dermatology Icahn School of Medicine at Mount Sinai New York, New York, USA

Katherine Hrynewycz, BS, MD Dermatology Resident Department of Dermatology Indiana University Indianapolis, Indiana, USA

Sa Rang Kim, MD Department of Dermatology Yale School of Medicine New Haven, Connecticut, USA

Sylvia Hsu, MD Professor and Chair Department of Dermatology Temple University Lewis Katz School of Medicine Philadelphia, Pennsylvania, USA Michael J. Huether, MD Medical Director Mohs Micrographic Surgery Arizona Skin Cancer Surgery Center, P.C. Tucson, Arizona, USA Michael J. Isaacs, MD Physician Department of Dermatology Indiana University School of Medicine Indianapolis, Indiana, USA Michael S. Kaminer, MD Associate Clinical Professor Department of Dermatology Yale Medical School New Haven, Connecticut, USA; Assistant Clinical Professor Department of Dermatology Brown Medical School Providence, Rhode Island, USA Prasanthi Kandula, MD Department of Dermatology SkinCare Physicians Chestnut Hill, Massachusetts, USA Swetha Kandula, MD, FAAD Founder Dermatology and Skincare Arts Parsippany, New Jersey, USA Sewon Kang, MD, MPH Noxell Professor and Chairman Department of Dermatology Johns Hopkins School of Medicine Baltimore, Maryland, USA Marshall B. Kapp, JD, MPH Director and Professor Emeritus Center for Innovative Collaboration in Medicine and Law Florida State University Tallahassee, Florida, USA

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Melanie Kingsley, MD Director of Cosmetic Dermatology and Laser Surgery Department of Dermatology Indiana University School of Medicine Indianapolis, Indiana, USA Sandra R. Knowles, BScPhm [Retired] Drug Information Pharmacist Department of Pharmacy Sunnybrook Health Sciences Centre Toronto, Ontario, Canada John Y.M. Koo, MD Professor Psoriasis and Skin Treatment Center University of California San Francisco, California, USA Carol L. Kulp-Shorten, MD Clinical Professor of Medicine (Dermatology) Departments of Medicine/Dermatology University of Louisville School of Medicine Louisville, Kentucky, USA Megan N. Landis, MD Clinical Associate Professor of Dermatology Department of Medicine Division of Dermatology University of Louisville Louisville, Kentucky, USA; Dermatologist Department of Dermatology The Dermatology and Skin Cancer Center of Southern Indiana Corydon, Indiana, USA Mark G. Lebwohl, MD Chairman Department of Dermatology Icahn School of Medicine at Mount Sinai New York, New York, USA Erica B. Lee, MD Department of Internal Medicine Santa Barbara Cottage Hospital Santa Barbara, California, USA

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Contributors

Katherine B. Lee, MD Assistant Clinical Professor Department of Dermatology University of California, Irvine Irvine, California, USA; Medical Director Halcyon Dermatology Laguna Hills, California, USA Amy B. Lewis, MD Clinical Assistant Professor Department of Dermatology Yale University School of Medicine New Haven, Connecticut, USA Geoffrey F.S. Lim, MD Medical Director Mohs Micrographic Surgery and Dermatologic Oncology OptumCare Medical Group Colorado Springs, Colorado, USA Henry W. Lim, MD Former Chair Department of Dermatology Henry Ford Hospital; Senior Vice President for Academic Affairs Henry Ford Health System Detroit, Michigan, USA Benjamin N. Lockshin, MD Director of the Clinical Trials Center U.S. Dermatology Partners Rockville, Maryland, USA; Assistant Professor Department of Dermatology Georgetown University Washington, Maryland, USA Thomas A. Luger, MD Professor of Dermatology Department of Dermatology University of Münster Münster, Germany Jacquelyn Majerowski, MD, BS Resident, PGY-4 Department of Dermatology Medical College of Wisconsin Milwaukee, Wisconsin, USA Lawrence A. Mark, MD, PhD Associate Professor of Clinical Dermatology Department of Dermatology Indiana University School of Medicine Indianapolis, Indiana, USA Dana Marshall, MD, FAAD Board Certified Dermatologist Klinger and Marshall Dermatology Gretna, Louisiana, USA

David Martell, DO Chief of Dermatology Department of Medicine Irwin Army Community Hospital Fort Riley, Kansas, USA Rachel R. Mays, BSc Research Associate Department of Dermatology Mediprobe Research Inc. London, Ontario, Canada Linda F. McElhiney, PharmD, RPh, MSP Team Lead Compounding Pharmacist Compounding Pharmacy Indiana University Health Indianapolis, Indiana, USA Ginat W. Mirowski, DMD, MD Adjunct Associate Professor Department of Oral Pathology, Medicine Radiology Indiana University School of Dentistry; Clinical Professor Department of Dermatology Indiana University School of Medicine Indianapolis, Indiana, USA Shoko Mori, MD Research Fellow Dermatology Service Memorial Sloan Kettering Cancer Center New York, New York, USA Kiran Motaparthi, MD Associate Professor Department of Dermatology University of Florida College of Medicine Gainesville, Florida, USA Uyen Ngoc Mui, MD Clinical Research Fellow Department of Dermatology Center for Clinical Studies Houston, Texas, USA Christian Murray, MD, FRCPC Associate Professor Departments of Dermatology/Medicine University of Toronto Toronto, Ontario, Canada Colton Nielson, MD Resident Physician Department of Dermatology University of Florida Gainesville, Florida, USA Megan H. Noe, MD, MPH, MSCE Clinical Instructor Department of Dermatology University of Pennsylvania Philadelphia, Pennsylvania, USA

Contributors

Ginette A. Okoye, MD Professor and Chair Department of Dermatology Howard University College of Medicine Washington, District of Columbia, USA

Dana L. Sachs, MD Professor Department of Dermatology University of Michigan Ann Arbor, Michigan, USA

Cindy England Owen, MD, MS Associate Clinical Professor Department of Dermatology University of Louisville Louisville, Kentucky, USA

Naveed Sami, MD Professor Departments of Internal Medicine and Dermatology University of Central Florida Orlando, Florida, USA

Timothy Patton, DO Assistant Professor of Dermatology Department of Dermatology University of Pittsburgh Pittsburgh, Pennsylvania, USA

Marty E. Sawaya, MD, PhD President Department of Dermatology Sujo Co. Ocala, Florida, USA

Warren W. Piette, MD Chair Division of Dermatology Department of Internal Medicine John H. Stroger, Jr. Hospital of Cook County; Professor Department of Dermatology Rush University Medical Center Chicago, Illinois, USA

Courtney R. Schadt, MD Associate Professor Division of Dermatology University of Louisville Louisville, Kentucky, USA

Sahand Rahnama-Moghadam, MD, MS Assistant Professor of Dermatology Department of Dermatology Indiana University Indianpolis, Indiana, USA Sarika Manoj Ramachandran, MD, FAAD Assistant Professor Yale University School of Medicine New Haven, Connecticut, USA Elizabeth A. Rancour, MD Dermatologist Private Practice Missouri Dermatology Laser and Vein Center St. Louis, Missouri, USA Jaggi Rao, MD, FRCPC Board Certified Dermatologist Clinical Professor of Medicine University of Alberta Edmonton, Alberta, Canada Misha Rosenbach, MD Associate Professor of Dermatology and Internal Medicine Vice Chair, Education and Training Director, Dermatology Inpatient Consult Service Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania, USA Katherine Roy, MD Dermatologist, Dermatopathologist Dermatology Group of the Carolinas Concord, North Carolina, USA

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William Schaffenburg, MD Department of Dermatology Walter Reed National Military Medical Center Bethesda, Maryland, USA Bethanee J. Schlosser, MD, PhD Assistant Professor Department of Dermatology Northwestern University Chicago, Illinois, USA Sahil Sekhon, MD Resident Physician Department of Dermatology Howard University Washington, District of Columbia, USA Vidhi V. Shah, MD Department of Dermatology University of South Florida Tampa, Florida, USA Lori E. Shapiro, MD, FRCPC Staff Physician Department of Dermatology Department of Clinical Pharmacology Drug Safety Clinic Sunnybrook Health Sciences Centre Toronto, Ontario, Canada Neil H. Shear, BASc, MD, FRCPC, FACP Professor Department of Medicine (Dermatology, Clinical Pharmacology) University of Toronto; Dermatologist-in-Chief Department of Dermatology Sunnybrook Health Sciences Centre Toronto, Ontario, Canada

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Contributors

Michael Sheehan, MD Dermatology Physicians Inc. Columbus, Indiana, USA Eric L. Simpson, MD, MCR Professor Department of Dermatology Oregon Health and Science University Portland, Oregon, USA Alexandra Snodgrass, MD Department of Dermatology University of Florida College of Medicine Gainesville, Florida, USA Nowell Solish, MD FRCP Assistant Professor Department of Dermatology University of Toronto Toronto, Ontario, Canada Ally-Khan Somani, MD, PhD Assistant Professor, Director of Dermatologic Surgery and Cutaneous Oncology, Director of Micrographic Surgery and Dermatologic Oncology Dermatology, Adjunct Assistant Professor of Otolaryngology Department of Otolaryngology-Head and Neck Surgery Indiana University School of Medicine Indianapolis, Indiana, USA

Stephen K. Tyring, MD, PhD, MBA Clinical Professor Department of Dermatology University of Texas Health Science Center; Medical Director Department of Dermatology Center for Clinical Studies Houston, Texas, USA Kaitlin Vogt-Schiavo, MD Department of Dermatology Indiana School of Medicine Indianapolis, Indiana, USA Raj Vuppalanchi, MBBS Professor of Medicine Department of Medicine–Gastroenterology Indiana University School of Medicine Indianapolis, Indiana, USA Steve Q. Wang, MD Director of Dermatologic Surgery and Dermatology Dermatology Service Memorial Sloan Kettering Cancer Center New York, New York, USA Gillian Weston, MD Department of Dermatology University of Connecticut Health Center Farmington, Connecticut, USA

Najwa Somani, MD, FRCPC Assistant Professor Department of Dermatology Indiana University School of Medicine Indianapolis, Indiana, USA

Stephen E. Wolverton, MD Theodore Arlook Professor of Clinical Dermatology Department of Dermatology Indiana University School of Medicine Indianapolis, Indiana, USA

Bruce Strober, MD, PhD Department of Dermatology Yale University New Haven, Connecticut, USA

Jashin J. Wu, MD Founder and Course Director San Diego Dermatology Symposium May 29-31, 2020; Founder and CEO Dermatology Research and Education Foundation Irvine, California, USA

Mathias Sulk, MD Department of Dermatology University of Münster Münster, Germany Kathleen C. Suozzi, MD Assistant Professor, Director, Aesthetic Dermatology Department of Dermatology Yale School of Medicine New Haven, Connecticut, USA Michael D. Tharp, MD Chair and Professor Emeritus Department of Dermatology Rush University Medical Center Tampa, Florida, USA Mary M. Tomayko, MD, PHD Associate Professor Departments of Dermatology and Pathology Yale University School of Medicine New Haven, Connecticut, USA

Ashley Wysong, MD, MS Founding Chairman William W. Bruce MD Distinguished Chair of Dermatology Department of Dermatology University of Nebraska Medical Center Omaha, Nebraska, USA John Zic, MD, MMHC Professor of Dermatology Department of Dermatology Vanderbilt University Medical Center Nashville, Tennessee, USA Jeffrey P. Zwerner, MD, PhD Assistant Professor Department of Dermatology Vanderbilt University Nashville, Tennessee, USA

Preface

This fourth edition of Comprehensive Dermatologic Drug Therapy has been both a challenge and a joy to edit. The challenge has been primarily in keeping up with the rapidly changing landscape of dermatologic therapy. The joy has been the continued refinement of an approach to summarizing vast quantities of information on dermatologic drugs in various formats that have been consistently popular with readers. This preface will include describing new chapters, appendices, and special features to enhance learning and retrieval of information in this book. Counting the original book, Systemic Drugs for Skin Diseases, published in 1991, the contents have grown from 17 chapters to 70 chapters in this fourth edition of Comprehensive Dermatologic Drug Therapy.

New chapters in this edition Chapter 5

Chapter 28

Medical decisionmaking principles PDE-4 inhibitors and JAK inhibitors IL 17 inhibitors

Chapter 29

IL 23 inhibitors

Chapter 31

Other biologic agents Hedgehog inhibitors

Chapter 18

Chapter 38

apremilast, tofacitinib secukinumab, ixekizumab, brodalumab guselkumab, tildrakizumab, risankizumab dupilumab, omalizumab, newer agents vismodegib, sonidegib

New appendices in this edition Appendix 1 Core questionsa for understanding systemic dermatology drugs (“Review test”) Section 1—Pharmacology basic science (67 questions) Section 2—Clinical use (75 questions) Section 3—Severe adverse effects (61 questions) Section 4—Less serious adverse effects (24 questions) Section 5—Drug safety monitoring (27 questions)

Section 6—Drug interactions (20 questions)b Section 7—Miscellaneous issues (6 questions) Appendix 2 The most potentially serious drug interactions contains 35 categories of serious/potentially life-threatening drug interactions condensed from the almost 30 fully updated drug interaction tables throughout this book.

New features in this edition • Drug Risks Profile boxes—at a glance the reader can quickly review a drug’s (a) Contraindications, (b) Boxed Warnings, (c) Warnings & Precautions, and (d) Pregnancy Prescribing Status (both traditional ratings and our summation of 2015 US Food and Drug Administration updates) • General updates—include (a) typically 2 to 4 new questions at the beginning of each chapter, and (b) substantial updating of references in all chapters

Traditional features continued in this edition • Monitoring guidelines boxes: This feature has been a long-term favorite for clinicians • Drug interactions tables: These fully updated tables are derived from Facts and Comparisons e-answers and Hansten and Horn’s Top 100 Drug Interactions databases, formatted in a new fashion with interactions listed with overall descending order of risk • Drug structures • Drug mechanism flow diagrams • Key pharmacology concepts • Adverse effects boxes … and many other features continued from prior book editions! Enjoy the learning and information retrieval process! Stephen E. Wolverton, MD (Senior Editor, SEW) Jashin J. Wu, MD (Associate Editor, JJW)

a280

open-ended high-yield questions selected from the roughly 800 questions at the beginning of each chapter, many of which have 2 to 4 components to the questions. Each question lists the book page number(s) for the answer. bSee also Appendix 2 for the highest-risk drug interactions

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Acknowledgments

We would like to sincerely thank and applaud the following individuals for their energetic and kind support of our journey through the book development and editorial process for the fourth edition of Comprehensive Dermatologic Drug Therapy. We are indebted to all of you for your time and expertise. I am very grateful for the expert assistance from my Associate Editor Jashin J. Wu, MD. Jay was the primary editor for 12 chapters including all but one of the six new chapters. Jay’s extensive experience in clinical trials was of great value!

To Elsevier We are most grateful to the book Acquisitions Editors Charlotta Kryhl and Nancy Duffy, the Senior Content Development Specialists Humayra Khan and Rae Robertson and the Project Manager Beula Christopher. These individuals have been remarkable in the author communications, attention to detail in editing, and accommodating to our planning strategies and subsequent adjustments. Thanks to Elsevier for the broader role in oversight from the beginning of book development through marketing the final product.

To the Indiana University Department of Dermatology My colleagues (current and past) from Indiana University Department of Dermatology who contributed chapters: Candace Broussard-Steinberg, Gabriella Duprat, Jeff Gehlhausen, Daniel Grove, Anita Haggstrom, Kate Hrynewicz, Michael Isaacs, Prasanthi Kandula, Swetha Kandula, Melanie Kingsley, Kathy Lee, Ben

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Lockshin, Lawrence Mark, Ginat Mirowski, Sahand Rahnama, Elizabeth Rancour, Kaitlin Schiavo, Michael Sheehan, Ally-Khan Somani, and Najwa Somani.

To the ‘States’ and the World (the authors) The 128 authors for this edition responded very, very well to the task of updating earlier chapters and creating totally new ones. These authors responded in a superb fashion to the challenges we set for them. In particular, we wish to highlight the following individuals: • The five authors who contributed to all five versions of the books I have edited (including the original title Systemic Drugs from Skin Diseases, 1991 edition): Jeff Callen, Charles Camisa, Loree Davis, Marshall Kapp, and Carol Kulp-Shorten. • The international cast of 12 authors from Canada and Europe: Stewart Adams, Robert Bissonnette, Tobias Goerge, Aditya Gupta, Sandra Knowles, Thomas Luger, Christian Murray, Jaggi Rao, Lori Shapiro, Neil Shear, Nowell Solish, and Mathias Sulk. • The senior authors who contributed to two chapters: Jeff Callen, Charles Camisa, Seth Forman, Melanie Kingsley, John Koo, Megan Landis, Ben Lockshin, Kiran Motaparthi, Katherine Roy, and Neil Shear. Thanks to all remaining authors who took time away from their full-time roles as clinicians and educators, while providing fresh ideas along with tremendous personal experience and expertise for the remaining chapters of this fourth edition of Comprehensive Dermatologic Drug Therapy. We acknowledge the entire list of authors who spent countless of hours writing and editing their chapters for this textbook.

PART I

Introduction

1

Basic Principles of Pharmacology STEPHEN E. WOLVERTON

QUESTIONS Q1.1 What are the simplest definitions of ‘pharmacokinetics’, ‘pharmacodynamics’, and ‘pharmacogenetics’? (Pg. 1, Table 1.1)

Q1.7 What are several important examples of active drug and active metabolite relationships? (Pg. 7, Table 1.9)

Q1.2 What are several drugs or drug families for which the absorption may be altered by (1) food, (2) cations such as iron, calcium, and magnesium, and (3) variations in gastric pH? (Pg. 2)

Q1.8 What are several of the most important examples of prodrug and active drug relationships? (Pg. 8, Table 1.8)

Q1.3 What are some of the pros and cons to the decision of whether to calculate drug dose on (1) actual body weight, (2) ideal body weight? (Pg. 3)

Q1.9 Pertaining to drug excretion, (1) what are three important routes of drug excretion, and (2) what is the overall general change in the active drug properties that makes excretion possible? (Pg. 8)

Q1.4 What are several examples in which sustained exposure to a drug may give reduced positive or negative pharmacologic effects at the drug receptor level? (Pg. 4, Table 1.4)

Q1.10 What are five of the most important basic components that determine percutaneous absorption of topical medications in general? (Pg. 8)

Q1.5 What are several of the most important agonists and antagonists at the level of specific receptors? (Pg. 4, Table 1.5)

Q1.11 What are the some of the additional cutaneous properties and therapeutic maneuvers that alter the degree of percutaneous absorption in individual patients? (Pg. 9, Table 1.10)

Q1.6 What are several of the most important examples in which drugs inhibit specific enzymes? (Pg. 6, Table 1.6)

Introduction This chapter is a relatively brief overview of basic principles of pharmacology, intended as a primer to maximize understanding of the remaining chapters of the book. There is by design some overlap with other chapters in the book, in order to address relevant issues from a number of vantage points. Of particular relevance to this chapter are the following: Chapter 2 Principles for Maximizing the Safety of Dermatologic Drug Therapy; Chapter 62 Hepatotoxicity of Dermatologic Drug Therapy (contains detailed information on hepatic metabolism of drugs); and Chapter 66 Drug Interactions. The reader is encouraged to pursue further detailed information and references (cited in the respective chapters for specific drugs) for drug examples used to illustrate basic principles of pharmacology in this chapter. In this chapter, only a bibliography format for references on pharmacologic general principles is used. The primary focus of this chapter will be on pharmacologic principles related to systemic drugs. A relatively brief section on percutaneous absorption will conclude the chapter. The basic goal

of this chapter (and for the rest of the book) is to describe and illustrate pharmacologic principles that will enable the clinician to maximize the efficacy and minimize the risk (adverse effects [AE], drug interactions) of dermatologic drug therapy. It is my hope that this chapter will provide a broad foundation for true understanding of pharmacology to enable clinicians to achieve: 1. More efficient assimilation of new information on medications; 2. Adaptability to the many unpredictable responses of patients to medications; 3. Better long-term retention of important information on all aspects of drug therapy.

Outline for the Chapter  Q1.1  Traditionally, discussions on basic pharmacology divide the topic into two domains (Table 1.1): pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body). As a relatively novel way of presenting this information, I will discuss topics in sequence as seen through the 1

2

PA RT I

Introduction

TABLE Three ‘Entry Level’ Definitions 1.1

TABLE Pharmacokinetics—Major Components 1.2

Term

Definition

Component

Most Important Issues

Pharmacokinetics

What the body does to the drug—from entry into the body until excretion of the drug and/or its metabolites

Absorption

Pharmacodynamics

What the drug does to the body—once at site of action; from receptor binding through the definitive effect (desired or adverse)

Relatively lipophilic drugs are more optimally absorbed through the gastrointestinal tract; lipophilic or hydrophilic drugs are relatively equal for parenteral absorption

Distribution

Body compartments to which the drug is dispersed; important subcomponents include fatty tissues and blood–brain barrier

Bioavailability

Percentage of administered drug reaching circulation; also relates to free (active drug) vs proteinbound drug (inactive drug)

Metabolism

Lipophilic drugs are converted to more hydrophilic metabolites to enable excretion

Excretion

The above conversion to hydrophilic metabolites allows renal or biliary excretion; other synonyms—clearance, elimination

Pharmacogenetics

Interindividual genetic alterations that produce variations in both pharmacokinetic and pharmacodynamic aspects of drug therapy

‘eyes’ of the drug as it progresses through the human body. In broad strokes, the sequence will be: 1. Pharmacokinetics (part I—absorption, distribution, bioavailability): the drug must enter the body, travel to, and be ‘available’ at the site of desired pharmacologic action; 2. Pharmacodynamics: the drug interacts with a receptor/effector mechanism, producing both desirable and undesirable effects; 3. Pharmacokinetics (part II—metabolism, excretion): the drug and/or its metabolites must leave the body. Each of the above steps has a number of variables (with both predictable and unpredictable components) for which the clinician should have at least a baseline working knowledge. These variables will be presented and illustrated under each chapter heading that follows.

Pharmacokinetics—Part I (Tables 1.2 and 1.3) Drug Absorption (The Drug has to be Absorbed and Enter Circulation) The routes of drug administration most pertinent to dermatology, in order of descending frequency of use, are topical, oral, intralesional, and intramuscular. Intravenous drug administration is uncommonly ordered by the dermatologist. Typically, drugs must be relatively lipophilic (nonionized, nonpolar) to ‘enter’ the body by topical or oral routes, whereas relatively hydrophilic (ionized, polar) drugs can still ‘enter’ by intramuscular and intravenous routes. Upon absorption, drugs still must traverse other cell membranes in order to reach the intended destination(s). Again, a drug with lipophilic qualities is rewarded by the ability to traverse these lipid bilayers in order to arrive at the site of desired pharmacologic action. Several other variables may affect the absorption of drugs by oral administration. Q1.2 Certain drugs are absorbed less efficiently in the presence of food. In descending order, the impact of food on tetracycline family drug absorption is as follows: tetracycline > doxycycline > minocycline. Divalent and trivalent cations in milk (calcium), various traditional antacids (aluminum-, magnesium-, calcium-containing), and iron-containing products can reduce the absorption of the above tetracyclines, as well as fluoroquinolone antibiotics. Gastric pH is yet another variable that influences drug absorption. An example would be the necessity for

These components as related to oral (enteral) or parenteral administered drugs.

a relatively low gastric pH for ketoconazole and itraconazole to be optimally absorbed, whereas gastric pH is not a critical determinant for fluconazole absorption. The above absorption variables are the basis for a number of drug interactions that do not involve the cytochrome P-450 (CYP) system. A few other points are worth considering under this heading. Some drugs have negligible absorption with oral administration, yet can have a pharmacologic effect in the gastrointestinal (GI) tract. Several examples would be the use of oral cromolyn sodium (Gastrochrome) for the GI manifestations of mastocytosis, as well as the use of nystatin for reduction of bowel Candida levels. A number of medications are available in sustained-release preparations, in which the drug vehicle is modified to allow a steady, slow rate of drug absorption. Finally, the addition of a vasoconstrictor (epinephrine) to local anesthetics will slow absorption of the anesthetic and, therefore, prolong the duration of anesthesia after intralesional injection of the anesthetic.

Distribution (The Drug has to Travel to the Site of Intended Action or to a Reservoir) This somewhat mundane component of pharmacokinetics has several applications in dermatologic therapeutics. With oral administration of drugs for dermatologic purposes, there are at least four compartments of great interest to which a drug can be distributed: 1. Circulation: important to widespread drug effects, both desirable and adverse; 2. Cutaneous: logically of central importance to the desired pharmacologic effects; 3. Fatty tissue: at both cutaneous and internal sites; very important to highly lipophilic drugs, creating a ‘reservoir’ for prolonged release of the drug (as with etretinate); 4. Past the ‘blood–brain barrier’: of importance to dermatology primarily for lipophilic drugs with the potential for sedation or other central nervous system AE (first-generation H1 antihistamines, sedation; minocycline, dizziness).

CHAPTER 1

Basic Principles of Pharmacology

3

TABLE Definitions and Concepts Central to Understanding Pharmacokinetics 1.3

Term

Definition

Bioactivation

Either (1) conversion of prodrug to any active drug, or (2) conversion of the active drug to a reactive, electrophilic metabolic intermediate

Bioequivalencea

Generally referring to overall ‘equal’ bioavailability between two comparable drugs; usually between generic and trade name formulations of a drug

Biotransformation

In general, the metabolic change of a lipophilic drug to a more hydrophilic metabolite allowing renal or biliary excretion

Blood–brain barrier

Protective mechanism for brain neurons; due to tight junctions (and lack of intercellular pores) in brain capillaries; highly lipophilic drugs may ‘overcome’ this barrier

Detoxification

The metabolic conversion of a reactive, electrophilic intermediate to a more stable, usually more hydrophilic compound

Enteral

GI administration of a drug

Enterohepatic recirculation

Sequence of initial GI absorption of drug followed by hepatic excretion into bile and small bowel, followed by subsequent GI reabsorption

First-pass effect

Drugs which have significant metabolism in the liver, before widespread systemic distribution—occurs after GI absorption, by way of portal vein to liver

Half-life

Duration of time for 50% of the absorbed and bioavailable drug to be metabolized and excreted

Parenteral

Literally ‘around enteral’; either intravenous, intramuscular, or subcutaneous administration

Pharmacogenetics

The inherited aspects of drug pharmacokinetics and pharmacodynamics which alter the likelihood of various pharmacologic effects (positive or negative)

Prodrug

A pharmacologically inactive precursor of the biologically active ‘drug’

Steady state

A balance between the amount of drug being absorbed and the amount being excreted; in general the time to reach steady state is four to five ‘half-lives’

Terminal elimination

Elimination/clearance of drug from all body compartments to which the drug is distributed

Therapeutic index

The ratio of (1) the drug dose required to give a desired pharmacologic response, to (2) the drug dose that leads to significant adverse effects

Therapeutic range

Range of circulating drug levels deemed to give optimal efficacy and minimal adverse effects

Tissue reservoirs

Body locations to which a given drug is distributed, from which the drug is very slowly released—includes sites such as fatty tissues, stratum corneum

aThe

US Food and Drug Administration definition for ‘bioequivalence’ requires that the bioavailability of the proposed generic drug must have a 95% confidence interval between 80% and 120% of the trade name drug’s bioavailability. GI, Gastrointestinal.

Fortunately, there are alternatives to the above drugs that do not readily cross the blood–brain barrier (second-generation H1 antihistamines; doxycycline, tetracycline). Q1.3 Many systemic drugs discussed in this book have dosages based on body weight. Included are drugs with doses calculated per kilogram of body weight (isotretinoin, etretinate) and dose calculated per meter squared (bexarotene—Targretin). The question arises as to what to do with dosage calculations for very obese patients. There are both drug cost implications and potential AE implications for very high drug doses. I tend to calculate dosages based more on ‘ideal weight’ for several reasons. Aside from treatment of panniculitis, there are virtually no indications for which the site of desired pharmacologic effect is in fatty tissue. Highly lipid-soluble drugs are readily distributed to fatty tissues, but when a steady state is reached, there is steady release back into the circulation. When considering efficacy, risk, and cost, all three point toward maximizing the dosage using calculations based on ideal (or close to ideal) body weight (IBW),

perhaps allowing for a small ‘fudge factor’ on the high side for very heavy patients who do not respond to traditional doses. One set of formulas from the life insurance industry for calculating ‘ideal weight’ is as follows: (1) females IBW = 100 lb for 5 ft tall + 5 lb/inch over 5 ft, and (2) males IBW = 106 lb for 5 ft tall + 6 lb/inch over 5 ft, and (3) an upward ‘adjustment’ up to 10% based on a ‘large frame.’ Conceptually, there are three drug ‘reservoirs’ of significant interest to dermatology. The first is in systemic circulation, in the form of drug-protein binding. The bound drug is pharmacologically inactive, whereas the unbound drug = free drug = pharmacologically active drug. Acidic drugs are most commonly bound to albumin, whereas basic drugs bind preferentially to α-1 acidic glycoprotein. There are noteworthy exceptions regarding lipophilic drugs with intracellular physiologic receptor–effector systems such as corticosteroids (CS) and retinoids. There is a large circulatory reservoir for highly protein-bound drugs such as methotrexate. Sudden increases in the free drug levels due to displacement

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Introduction

of methotrexate from circulatory protein-binding sites by aspirin, nonsteroidal anti-inflammatory drugs, and sulfonamides can markedly increase the risk for pancytopenia (although the body can adjust to this drug displacement over time). The second drug reservoir of interest is in various fatty tissues (including, but not limited to, subcutaneous fat) for highly lipophilic drugs, as discussed in the preceding paragraph. The third drug reservoir (the stratum corneum) pertains just to percutaneous absorption for topically applied medications. In all three settings the free drug and the drug in the reservoir are in equilibrium. As the free drug is metabolized and excreted, corresponding amounts of the drug in these tissue and circulatory reservoirs are released into the free/ active drug fraction.

Bioavailability (The Drug has to be ‘Available’ at The Site of Intended Action) Bioavailability is expressed as the percentage of the total drug dose administered that reaches the circulation. For a drug taken orally, the ‘first-pass effect’ of hepatic metabolism reduces bioavailability. The bioavailability calculations include both free and bound forms of the drug. A systemic drug with a relatively low bioavailability is acyclovir; the prodrug for acyclovir, valacyclovir, has at least three times greater bioavailability. At the other end of the spectrum are the fluoroquinolones, for which oral absorption (and resultant bioavailability) is so complete that the oral and intravenous doses for many members of this drug group are identical. A more optimal method (if it were more practical) would be to calculate bioavailability at the site of intended action; for drugs discussed in this book, it would be based on tissue levels at the site of intended action, the various skin structures. At present such ‘ideal’ bioavailability calculations are not routinely available. For most chapters in this book that discuss systemic drugs there are tables that present data for the following: (1) % bioavailable and (2) % protein binding. The ‘% bioavailable’ is typically factored into ideal oral drug dosage calculations, which will produce circulating drug levels in a reasonably safe and effective ‘therapeutic range.’ The ‘% protein binding’ is important to the subject of drug interactions as previously discussed, with methotrexate as an important example. Changes in albumin levels in disease states such as severe liver or renal disease will often necessitate drug dosage adjustments for drugs (such as methotrexate) that are highly protein bound. Creating drug formulations with a more optimal bioavailability is a daunting task for the pharmaceutical industry. In the past few decades there have been updated formulations of older drugs with higher bioavailability, more predictable bioavailability, or both. For drugs with a relatively narrow therapeutic index (cyclosporine, methoxsalen), improved predictability of the drug absorption and resultant bioavailability are very important. The release of Neoral and Gengraf (in place of the previous cyclosporine formulation, Sandimmune) is an example for both improved % bioavailability and more predictable bioavailability of the newer formulation. Likewise, Oxsoralen Ultra demonstrates improvement in both of these two parameters. In a separate example, the need for improved efficacy from griseofulvin led to the progression from the original griseofulvin formulations → microsize formulations → ultramicrosize formulations. Each step of this progression resulted in improved bioavailability and smaller griseofulvin dosages required for an adequate therapeutic response.

Pharmacodynamics (The Drug Produces the Desired Pharmacologic Effect) The subject of pharmacodynamics is very complicated. In essence, this topic is the ‘basic science’ behind drug mechanisms of action. Considering all the diverse mechanisms of actions discussed in this book (let alone the diversity of drug mechanisms in the entirety of medicine), it is not possible to summarize general principles behind all of them. In contrast, it is possible to cover a few areas of central importance to understanding pharmacodynamics. These include the concepts of drug receptors, enzyme inhibition by drugs, signal transduction, and transcription factors.

Definitions (Table 1.4) In general, the definitions used in pharmacodynamics tend to be less familiar to most clinicians than the comparable terms in pharmacokinetics. These terms overall tend to relate to factors that: 1. Address aspects of drug binding to receptor (ligand, affinity); 2. Relay the drug ‘signal’ to the definitive effector mechanism (signal transduction, second messenger); 3. Increase the desired pharmacologic response (drug agonists, partial agonists); 4. Reduce an undesirable physiologic or pharmacologic response (drug antagonists or receptor blockers); or 5. Q1.4 Result in a loss of a desirable or undesirable pharmacologic response through repeated use (tolerance, cross tolerance, refractoriness, downregulation, tachyphylaxis). Only a proportion of these concepts can be realistically addressed in the remainder of this section on pharmacodynamics.

Drug Receptors The broadest definition of a drug receptor is given in Table 1.4. In this definition, any molecule to which a drug binds, thus initiating an effector mechanism leading to a specific pharmacologic response, is a drug receptor. In contrast, proteins involved in drug ‘protein binding’ are merely drug storage (reservoir) or transportation sites, and thus, are not receptors. The drug receptor subtypes that are easiest to characterize are cell surface receptors for endogenous neurohormonal ligands. Similar receptors are operant for various growth factors and other cytokines. Q1.5 Such ‘drug’ receptors are common targets in current therapeutic strategies and in drug development. In addition, lipophilic drugs easily absorbed through cellular membranes may have cytosolic drug receptors. Common examples using these cytosolic physiologic receptors include both systemic and topical versions of CS and retinoids. The ‘catch’ regarding receptors for these two drug categories is that both desirable (therapeutic effects) and undesirable (AE) effects are mediated through the same physiologic receptor. A ‘dissociation’ of the drug receptors for the therapeutic anti-inflammatory benefits of methotrexate (such as methionine synthetase) and AE (dihydrofolate reductase, [DHFR]) is of interest. Folic acid (folate) supplementation can competitively antagonize the DHFR inhibition of methotrexate and minimize the AE of methotrexate without compromising therapeutic benefits. A few examples of drugs that are either antagonists or agonists at well-defined cellular receptors are given in Table 1.5. Few drugs are ideally specific for a given drug receptor molecule. The ability of both tricyclic antidepressants (such

CHAPTER 1

Basic Principles of Pharmacology

TABLE Definitions and Concepts Central to Understanding Pharmacodynamics 1.4

Term

Definition

Active metabolite

A drug metabolite which retains the same/similar pharmacologic properties as the parent drug

Affinity (binding)

A physical measurement which reflects the attraction of the drug ligand to a given receptor molecule

Agonist

Drug which binds to a given receptor initiating an effector mechanism → pharmacologic response

Antagonist

Drug which binds to a receptor, but fails to activate the effector mechanism

Cross tolerance

(see Tolerance) Reduced pharmacologic effect when exposed to a new, chemically related drug

Downregulation

Reduced receptors number/availability, presumably due to a negative feedback mechanism

Inverse agonist

Drug which stabilizes receptors which have some constitutive activity to an inactive conformation

Ligand

Any molecule (drug) which binds to the drug receptor; binding can be by hydrogen bonds, ionic forces, or covalent forces

Partial agonist

Drug which binds to a receptor and weakly initiates an effector mechanism and resultant response

Receptor

The molecule to which the drug (ligand) binds to initiate its effector response; location can be cell membrane, cytosolic, or intranuclear

Refractoriness

(synonyms—desensitization, tachyphylaxis) Temporary lack of responsiveness to a drug, subsequent to prior drug efficacy

Second messenger

Biochemical mediator (commonly calcium or cyclic adenosine monophosphate) that serves to relay the signal initiated by the receptor/effector in signal transduction

Signal transduction

Cellular biochemical pathways which relays a second messenger ‘signal’ from the receptor to the effector mechanism

Tachyphylaxis

A diminished pharmacologic response after repeated drug administration; can be due to down regulation or receptor sequestration (transiently ‘unavailable’ to the drug)

Tolerance

Diminished effect (generally adverse effect) after repeated drug administration (most common is tolerance to sedating drugs such as antihistamines)

TABLE Pharmacodynamics—Selected Receptor Antagonists and Agonists 1.5

Drug/Drug Group

Receptor Affected

Biologic Outcome

Receptor Antagonists (Receptor ‘Blockers’) H1 antihistamines

H1 antihistamine receptor

Antagonize histamine effects via receptor—vasodilation, increased vascular permeability, etc.

H2 antihistamines

H2 antihistamine receptor

Antagonize histamine effects via receptor—decreased gastric acid secretion, suppressor (CD8) T-cell effects

Spironolactone

Androgen receptora

Antagonize testosterone and dihydrotestosterone effects via receptor— variable hair effects depending on scalp or face location; also reduced sebum secretion

Selective serotonin reuptake inhibitors

Serotonin transport protein

Antagonize serotonin reuptake mechanism (net effect increased persistence of serotonin as neurotransmitter)

Corticosteroids

Corticosteroid receptor

Augment both the desirable pharmacologic effects and the adverse effects mediated through same receptor

Calcipotriene

Vitamin D3 receptor

Augment vitamin D3 effects via receptor—include keratinocyte and fibroblast differentiation

Retinoids

Retinoic acid receptor (RAR) Retinoid X receptor (RXR)

Augment various vitamin A-mediated effects via gene response elements

Hormonal Receptor Agonists

aPrimary

pharmacologic (diuretic) effects of spironolactone are mediated through the mineralocorticoid receptor; antiandrogen effects are mediated via the androgen receptor for dihydrotestosterone and testosterone.

5

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Introduction

as doxepin) and first-generation H1 antihistamines (such as diphenhydramine, hydroxyzine) to also bind muscarinic anticholinergic receptors can produce objectionable anticholinergic AE such as dry mouth, blurred vision, and orthostatic hypotension. Relatively selective drug receptor binding was achieved in later ‘generations’ of related drug groups. Selective serotonin reuptake inhibitors (such as fluoxetine, sertraline) and secondgeneration H1 antihistamines (such as fexofenadine, loratadine) have had a significant improvement in the AE profile due to much more selective drug receptor binding. It is of interest to note that ‘tolerance’ to the sedative AE can occur with prolonged use of the first-generation H1 antihistamines.

nucleotide synthesis have significant potential for use in neoplastic diseases or as immunosuppressants in autoimmune dermatoses. A number of drugs representing antimicrobial agents for bacterial, viral, and fungal infections capitalize on vital enzyme systems, which are more readily inhibited in the infectious organism than in the human host. Finally, a number of drugs inhibit enzyme systems that contribute important downstream mediators to an inflammatory response. For all three categories of enzyme listed in this table, the drug receptor may be the enzyme itself (methotrexate and DHFR) or may work indirectly through another receptor/ effector mechanism (as with CS inhibition of phospholipase A2, probably mediated through lipomodulin-1).

Enzyme Systems Inhibited by Drugs

Signal Transduction and Transcription Factors

Q1.6 For comparison purposes, a number of specific examples for drugs that selectively inhibit an enzyme system are listed in Table 1.6. Drugs that inhibit enzyme systems of importance to

These two aspects of pharmacodynamics have a number of conceptual similarities, albeit with very distinctive mechanisms of action. Signal transduction is a series of intermediary steps in relaying a

TABLE Pharmacodynamics—Selected Examples of Enzymes that Specific Drugs Inhibit 1.6

Drug/Drug Group

Enzyme Inhibited

Biologic Outcome

Enzymes Important to DNA Synthesis Methotrexate

Dihydrofolate reductase

Reduced formation of fully reduced folate precursors for purine and thymidylate synthesis

Mycophenolate mofetil

Inosine monophosphate dehydrogenase type II

Inhibition of de novo pathway for purine (guanosine) nucleotide synthesis— preferentially affects various WBC subsets (other cells can utilize salvage pathway)

Enzymes Important to Microbial Growth and Survival Sulfonamides, dapsone

Dihydropteroate synthetase

Affects bacterial version of this enzyme far more readily than the mammalian enzyme; first step of two-enzyme pathway essential for folate reduction

Trimethoprim, methotrexate

Dihydrofolate reductase

Affects bacterial version of this enzyme far more readily than the mammalian enzyme; second step of two-enzyme pathway essential for folate reduction

Itraconazole, fluconazole

Lanosterol 14-α demethylase

Triazole inhibition of this enzyme inhibits formation of ergosterol, an essential component of fungal cell wall

Terbinafine, naftifine

Squalene epoxidase

Allylamine inhibition of this enzyme decreases ergosterol, and increases squalene accumulation

Acyclovir, valacyclovir, famciclovir

DNA polymerase

Triphosphorylated forms of these drugsa preferentially inhibit viral DNA polymerase >> human version of enzyme

Other Enzymes of Importance to Inflammatory Response Retinoids

Ornithine decarboxylase

This is rate-limiting enzyme in polyamine pathway, which is initiated by protein kinase C (PKC) activation

Dapsone

Myeloperoxidase

This enzyme in neutrophils and macrophages is essential to microbial killing by these cells (also in eosinophils)

Cyclosporine, tacrolimus

Calcineurin

This calcium-dependent signal transduction enzyme is key to increased IL-2 production dependent on NFAT-1b

Corticosteroids

Phospholipase A2

Inhibition probably mediated through lipomodulin-1; net effect is reduced prostaglandins, leukotrienes, and other eicosanoids which are important to inflammatory responses

Apremilast

Phosphodiesterase-4

Reduced inflammatory response through alteration of cAMP/cGMP ratio

aSee Table

1.8 regarding prodrug and active relationship of these drugs. (nuclear factor activated T-cells) is a transcription factor essential to increased T-cell production of IL-2 and upregulation of IL-2 receptors. cAMP, Cyclic adenosine monophosphate; cGMP; Guanosine monophosphate; DNA, Deoxyribonucleic acid; WBC, White blood cells. bNFAT-1

CHAPTER 1

drug-initiated signal or message to the definitive effector mechanism. Tremendous details on the various receptor/signal transduction categories (six main families) are beyond the scope of this chapter but are available in the Bibliography. This definitive effector mechanism is commonly accomplished through deoxyribonucleic acid (DNA) transcription and subsequent new protein translation. In many cases the signal transduction ‘passes through’ a DNA transcription factor. This sequence and the resultant overlap of topics is best illustrated by the so-called ‘signal one’ in activated T-cells upon T-cell receptor binding to antigen, which is amplified by subsequent IL-2 binding to the IL-2 receptor. The rough sequence of steps is as follows: (1) T-cell receptor binding to antigen, (2) CD3 molecule-based T-cell activation, and (3) calcineurinbased production of nuclear factor activated T-cell 1 (NFAT-1), a DNA transcription factor important to IL-2 upregulation. Cyclosporine and tacrolimus both interfere with this signal transduction pathway through inhibition of calcineurin activity, with a resultant decrease in activity of the transcription factor NFAT-1. Second messengers are also important to this discussion. Probably the two most important second messengers pertinent to pharmacology are calcium and cyclic adenosine monophosphate (cAMP). Calcium is an important component of the above T-cell signal transduction system in two locations; calcineurin is a calcium-dependent enzyme, with a calcium-binding protein (calmodulin) playing an important role as well. Although not directly related to dermatology, the role of cAMP as a second messenger in the beneficial effects of β-agonists in therapy of asthma is of interest. The concept of tachyphylaxis as defined in Table 1.4 has been well characterized for β-agonists used in this setting. Two more examples of important drugs and their effects on signal transduction (retinoids) and transcription factors (CS) can be presented. The polyamine pathway creates a process known as inflammatory hyperplasia, which is an important component of the pathogenesis of both psoriasis and various malignancies. Retinoids inhibit the activity of ornithine decarboxylase, the ratelimiting enzyme in the polyamine pathway. This signal transduction enzyme inhibition is important to the benefits of systemic retinoids in both psoriasis therapy and retinoid chemoprevention of cutaneous malignancies in solid organ transplantation patients. CS inhibit the actions of the transcription factor, nuclear factor κB (NFκB) by two mechanisms. CS both increase production of the inhibitor of NFκB (known as IκB) and directly bind to and inactivate NFκB. This transcription factor is pivotal in the upregulation of a multitude of cytokines of central importance in the inflammatory response to a wide variety of stimuli. There is tremendous amplification potential of the inflammatory response through this NFκB pathway. Likewise, a major portion of the anti-inflammatory benefits of CS (topical or systemic) are probably accomplished through the inhibition of this important transcription factor. It is unclear whether the relatively common occurrence of tachyphylaxis noted with class I topical CS relates to downregulation of receptors involved in this particular pathway.

This topic is extensively discussed in Chapter 62 Hepatotoxicity of Dermatologic Drug Therapy. A relatively brief synopsis will be presented here. Most drugs are metabolized by phase I (oxidation

7

reactions) and phase II (conjugation and detoxification reactions). The initial oxidation reactions in phase I are accomplished by various CYP isoforms, which are largely present in the liver (but also available in many other organ sites, including the skin and GI tract). The result of these enzymes is a somewhat more hydrophilic (water-soluble) metabolite, which may provide a site of attachment for subsequent conjugation reactions. To complicate matters, reactive electrophilic intermediates are often created, which in the absence of adequate phase II detoxification systems may induce important metabolic or immunologic complications (Table 1.7). Phase II conjugation reactions (glucuronidation, sulfonation, acetylation) and the various detoxification systems (such as glutathione and epoxide hydrolase) will generally accomplish the production of both significantly increased hydrophilicity of the drug metabolites and stabilization of the aforementioned reactive intermediates, respectively. Q1.7 It is important to note here that many drug metabolites retain the parent drug’s pharmacologic activity (Table 1.8). An example of this principle would be the itraconazole metabolite hydroxyitraconazole, which also has significant antifungal activity. In the great majority of drugs metabolism renders the drug inactive. The topic of pharmacogenetics largely addresses genetically based variations in the above metabolic enzyme systems. At times, these genetic alterations can explain idiosyncratic AE of medications. Examples pertinent to the above phase I and phase II metabolic systems include the following genetic polymorphisms: 1. CYP2D6 polymorphisms with at least 50-fold variation in the activity of this important isoform: One result is unexpected profound sedation from various antidepressants (including doxepin) and other sedating medications in ‘poor metabolizers.’ 2. ‘Slow acetylators’: One result of this polymorphism is more frequent occurrence of drug-induced lupus erythematosus.

TABLE Definitions Related to Adverse Effects 1.7

Term

Definition

Adverse effect

Negative or undesirable effect from a drug (either at toxic or pharmacologic drug doses)

Idiosyncratic

Unexpected adverse effect from a drug

Immunologic idiosyncrasy

Unexpected adverse effect from a drug occurring on an immunologic basis (usually due to hypersensitivity)a

Metabolic idiosyncrasy

Unexpected adverse effect from a drug occurring due to a metabolic byproduct (reactive intermediate)

Pharmacologic effect

Positive or negative effect from a drug, expected at normal doses and/or drug levels

Side effect

Synonym for adverse effect (prefer to use ‘adverse effect’ to address undesirable quality of drug effect)

Toxicity/toxic effect

Undesirable effects expected from a drug due to excessive doses and/or drug levels

Pharmacokinetics—Part II Metabolism (The Drug Becomes More Hydrophilic to Favor Renal and Biliary Excretion)

Basic Principles of Pharmacology

aConfusing

reality is that immunologic hypersensitivity may occur due to excessive quantities of a reactive metabolite, rendering immunogenic a previously normal endogenous protein (see Chapter 62 Hepatotoxicity of Dermatologic Drug Therapy).

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TABLE Some Examples of Prodrugs Important to 1.8 Dermatology

Prodrug

Active Drug

Antiviral Agents

TABLE Some Examples of Active Drug, Active 1.9 Metabolite Relationships

Active Drug

Active Metabolite(S)

Antihistamines

Valacyclovir

Acyclovir

Hydroxyzine

Cetirizine → levo-cetirizine

Famciclovir

Penciclovir

Loratadine

Desloratadine

Corticosteroids

Antidepressants

Prednisone

Prednisolone

Doxepin

Nordoxepin

Cortisone

Hydrocortisone (cortisol)

Citalopram

Escitalopram

Other Immunosuppressants

Antifungal

Azathioprine

6-mercaptopurine → 6-thioguanine

Mycophenolate mofetil

Mycophenolic acid

Cyclophosphamide

Phosphoramide mustard

Antihistamines Terfenadine

Fexofenadine

3. Glutathione depletion (which in part may be acquired due to malnutrition or HIV infections): this results in markedly increased risk of hypersensitivity to sulfonamide medications in these populations. The key research agenda for this important topic is the development of predictive tests to anticipate which patients are at increased risk for important AE from drugs. These tests would be analogous to the baseline glucose-6-phosphate dehydrogenase (G6PD) determinations for dapsone patients and baseline thiopurine methyltransferase determinations for azathioprine patients, which in both cases enables better prediction of patients at risk for important AE. Genetic predictive testing for polymorphisms of CYP2D6, 2C9, and 2C19 are currently commercially available. The most important numerical parameter under the heading of drug metabolism is the drug ‘half-life.’ The discussion of the multiple subtypes of drug half-life, such as terminal elimination half-life, is beyond the scope of this chapter. A given drug’s half-life is important in determining the time to reach a steady state once drug therapy is initiated (four to five half-lives) and the time for virtually complete drug clearance after drug therapy is discontinued (likewise at least four to five half-lives). Q1.8 One flaw of the linear model presented here for discussing pharmacodynamics between the two sections on pharmacokinetics relates to prodrugs (Table 1.9). These prodrugs are pharmacologically inactive until there is ‘metabolic’ conversion to the active drug, typically through hydrolysis of an ester or amine linkage. The conversion of prednisone (prodrug) to prednisolone (active form) is dependent on a hepatic-based enzyme, which in end-stage liver disease may not produce therapeutically adequate quantities of the active drug form prednisolone. Once the prodrug is metabolized to the active drug, the principles of interest follow through the distribution, bioavailability, and pharmacodynamics sections as with other drugs already in active form once absorbed.

Itraconazole

Hydroxyitraconazole

Excretion (The Relatively Hydrophilic Drug Metabolites Must Leave the Body) Q1.9 Conceptually there are three common routes by which systemically administered medications leave the body. These are (1) renal excretion, (2) biliary excretion of a more hydrophilic metabolite through the GI tract, and (3) orally administered medications may in part be excreted through the GI tract after failing to be absorbed. The excreted drug can be the parent drug, drug metabolites, or combinations of both. Relatively hydrophilic drugs can be excreted unchanged through the kidney. An example would be fluconazole, which because of its relatively hydrophilic properties has a significant portion of the administered drug excreted through the kidney unchanged. Relatively lipophilic drugs typically must be rendered more hydrophilic by the aforementioned phase I and II metabolic steps before excretion is possible through renal or biliary routes. In particular, greater hydrophilicity favors renal excretion, which has a much larger overall capacity for drug excretion than the hepatobiliary route. In reality, the drugs discussed in this book are frequently excreted by several of the above routes, both as free drug and as a variety of metabolites. Refer to the various ‘Pharmacology Key Concepts’ tables used for systemic drugs in this book for illustrations of this point. The reader should also be aware that many drugs conjugated in the liver, and excreted into bile, will subsequently undergo hydrolysis in the small intestine and be reabsorbed (enterohepatic recirculation) through many cycles. Eventually the definitive excretion may be through the kidney. It is very important to recognize that disease-induced or agedependent reduction in renal function should prompt the clinician to significantly reduce dosages of drugs with significant renal clearance. An example would be the increased risk for pancytopenia and other complications with methotrexate when standard doses are administered to patients with either disease- or agerelated reduction in renal function. Likewise, drugs that have significant liver metabolism and excretion should have dosage reductions with advanced liver disease.

Percutaneous Absorption General Principles There is a wealth of scientific and practical information in Tables 1.10 and 1.11. Q1.10 Probably the five most important

CHAPTER 1

Basic Principles of Pharmacology

9

TABLE Percutaneous Absorption Variables 1.10

Variable

Biologic Result

Drug Variables Concentration

PCA is directly related to concentration, and not volume of topical medication applied to a specific skin site

Lipophilicity

Most topically effective drugs are at least somewhat lipophilic

Molecular size

Most effective topical medications have a molecular weight < 600 (tacrolimus greater topical absorption than cyclosporine due to lower molecular weight)

Vehicle Variables (see Table 1.11) Lipid content

Ointment is strongest vehicle due to most optimal partition coefficient in transferring drug to stratum corneum lipids (solution typically weakest vehicle)

Irritancy

Irritating vehicles will alter skin barrier function and may ↑ PCA

Innate Skin Variables Stratum corneum thickness

Rate-limiting site for PCA; thickness of stratum corneum is inversely related to PCA

Cutaneous vasculature

Increased cutaneous vasculature can increase both local and systemic drug effects

Area of absorptive surface

Increased surface area to which drug is applied will ↑ PCA total overall, but not ↑ PCA at a specific site (concentration most important variable at a specific site)

Mucosal surfaces

Far less innate barrier function, generally less well-developed stratum corneum; consider that any mucosal route of administration can produce systemic effects

Diseased Skin Variables Inflamed skin

Overall ↑ PCA, due both to altered barrier function and increased vasodilation

Ulceration

Topical application responds as if systemic administration of medication (bacitracin or neomycin anaphylaxis risk after application to a leg ulcer)

Other Variables Additional skin hydration

Hydrating skin (by various means) before application of topical medication will ↑ PCA

Occlusion of medication

Topical occlusion locally (food wrap) or widespread (‘sauna suit’) with marked ↑ PCA; conceptually transdermal application of ‘systemic medications’ utilizes somewhat similar process

Age of patient

Increased total body surface area to body volume ratio in infants and young children; therefore, increased risk of systemic effects from topical therapy due to relatively high absorptive surface

PCA, Percutaneous absorption.

determinants of percutaneous absorption of topical dermatologic products are: 1. Stratum corneum thickness and integrity of ‘barrier function’; 2. Drug partition coefficient—the ability of the drug to ‘depart from’ the specific vehicle and enter the stratum corneum; 3. Drug diffusion coefficient—the ability of the drug (due to innate molecular properties) to penetrate through all layers of skin once in the stratum corneum; 4. Drug concentration—the specific drug concentration of a given topical product; and, 5. Superficial dermal vascular plexus—site of systemic absorption for topically applied drugs. Q1.11 Measures that increase percutaneous absorption can always be considered a ‘two-edged sword.’ The desired pharmacologic result is enhanced by these measures. For instance, use of a high-potency topical CS in an ointment base, after skin hydration, and with total body occlusion will do wonders for extensive psoriasis. The counterpoint is that all of these measures will markedly increase systemic absorption of the topical CS, potentially giving a net prednisone-like effect from the topical

CS. For a short period of time there will be relatively few tradeoffs. After 2 to 3 weeks or more, important systemic AE such as weight gain, fluid retention, hypertension, hypokalemia, leukocytosis, and cushingoid changes are all possible with this undesirable long-term approach to topical CS administration. It is important to note here that all topical drug absorption occurs via passive diffusion. Topical medications applied in several clinical settings can produce immediate hypersensitivity (Coombs-Gell type I) reactions. In particular, topical application to ulcerated skin can give the applied medication almost immediate access to systemic circulation. There have been reports of anaphylaxis to topical bacitracin or neomycin in this setting. Likewise, mucosal applications of medications (such as eyedrops, vaginal suppositories, and rectal foam or suppositories) can result in significant systemic levels of various drugs and freedom from ‘first-pass effect’ due to the small intestine and liver. Although the risk from topical application of medications to these above sites is usually small, the clinician should always be mindful of this systemic absorption potential.

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TABLE Clinical Comparisons of Various Vehicles—Generalities 1.11

Property

Ointments

Creams

Gels

Lotions/Solutions

Composition

Water in oil emulsion

Oil in water emulsion

Semisolid emulsion in alcohol base

Powder in water (some with oil component)

Relative potency

Strong

Moderate

Strong

Low

Hydration or drying properties

Hydrating

Somewhat hydration

Drying

Drying (variable)

Variability generic vs trade name

Relatively low

Potentially significant

Potentially significant

Potentially significant

Stage of dermatitis treated

Chronic

Acute to subacute

Acute to subacute

Acute

Sensitization risk

Very low

Significant

Significant

Significant

Irritation risk

Very low

Very low

Relatively high

Low to moderate

Body sites where most useful

Nonintertriginous

Virtually all sites

Oral, scalp

Scalp, intertriginous

Body sites to avoid

Face, groin, other skin folds

Sites with maceration

Fissures, erosions; also macerated skin

Fissures, erosions

Patient preference

Often dislike greasiness

High rate patient acceptance

Variable

High rate patient acceptance

Vehicles Much of the art and science of dermatology revolves around choosing the appropriate vehicle for topical medications (Table 1.11). In general, the choice of vehicle is just as important as choosing the proper active ingredient. Two common consequences of certain vehicles are the following: 1. Irritancy: most notably from high concentrations of propylene glycol; other ‘alcohols’ or certain acidic vehicle ingredients also may be irritants, particularly when applied to diseased skin with altered barrier function. 2. Contact allergy/sensitization: common with preservatives in various water-based (creams, lotions, solutions) topical products, and include various parabens along with ‘formalin releasers’ (such as quaternium-15, imidazolidinyl urea, and diazolidinyl urea). The astute clinician will be mindful of the potential AE of the vehicle, particularly if the patient fails to improve or worsens with topical therapy. The simplest and safest way to minimize the risk of these vehicle-induced AE is to choose topical products that lack the most common potential irritants and allergens. See Chapter 45 Topical Corticosteroids and Chapter 56 Irritants and Allergens: When to Suspect Topical Therapeutic Agents for additional information on this topic.

Tachyphylaxis In my experience, tachyphylaxis is a relatively common clinical event with very high-potency (class I) topical corticosteroids (TCS) and seldom seen with lower potency products. (See Chapter 4 Adherence with Drug Therapy for some ‘counterpoints’ on this controversial topic.) The measures previously discussed, which can produce excessive systemic absorption, also predispose to diminished therapeutic benefit from the topical drug over time. The clinician should be aware that continued daily or twice-daily

application of a class I TCS to minimally inflamed skin (without any other maneuvers to increase percutaneous absorption) at times leads to tachyphylaxis after 2 to 4 weeks of continuous therapy. The good news is that this is an easily reversible process, particularly if the clinician is mindful of the potential for tachyphylaxis. Weekend-only or alternate-day applications of these high-potency topical products typically prevents tachyphylaxis; a week or so off therapy altogether allows upregulation of the CS receptor molecules and a resultant return of the desired therapeutic benefit upon resumption of the high-potency TCS.

Transdermal Medication Formulations One final routine of topical administration of medications that is tangentially related to dermatology deserves mention here. The potential for certain drugs to have reduced bioavailability through excessive hepatic and small intestine first-pass metabolism can be circumvented by transdermal administration. An excellent example would be transdermal estrogen administration, which allows the drug to be absorbed directly into systemic circulation. This avoids the significant first-pass metabolism typical of orally administered estrogens, with resultant improved drug bioavailability. There are numerous other medications that can be administered in various transdermal delivery systems for steady, continuous percutaneous delivery of the active ingredient.

Summary Given the central importance of understanding percutaneous absorption, the interested reader is encouraged to pursue further information on this subject from the chapters listed in the Bibliography. Hopefully through the principles, clinical examples, and tables presented on this subject, all readers can achieve an adequate basic understanding of the most important concepts of percutaneous absorption and the importance of the drug

CHAPTER 1

vehicle to the optimal clinical response. Each chapter in the three major book sections on topical medications (Chapters 41–57) will expand on and illustrate these principles of percutaneous absorption.

Bibliography: Important Reviews and Chapters Systemic drugs Buxton ILO, Benet LZ. Pharmacokinetics: the dynamics of drug absorption, distribution, metabolism, and elimination. In: Brunton LL, Chabner BA, Knollman BC, eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. 12th ed. New York: McGraw Hill; 2011:17–39. Blumenthal DK, Garrison JC. Pharmacodynamics: molecular mechanisms of drug action. In: Brunton LL, Chabner BA, Knollman BC, eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. 12th ed. New York: McGraw Hill; 2011:41–72.

Basic Principles of Pharmacology

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Gonzales FJ, Coughtrie M, Tukey RH. Drug metabolism. In: Brunton LL, Chabner BA, Knollman BC, eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. 12th ed. New York: McGraw Hill; 2011:123–143. Relling MV, Giacomina KM. Pharmacogenetics. In: Brunton LL, Chabner BA, Knollman BC, eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. 12th ed. New York: McGraw Hill; 2011:145– 168. Percutaneous Absorption Burkhart C, Morell D, Goldsmith L. Dermatogic pharmacology. In: Brunton LL, Chabner BA, Knollman BC, eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. 12th ed. New York: McGraw Hill; 2011:1803–1832.

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Principles for Maximizing the Safety of Dermatologic Drug Therapy STEPHEN E. WOLVERTON

QUESTIONS Q2.1 What four words characterize the overall approach to maximizing drug safety, and what general concepts are represented by these words? (Pg. 12)

Q2.7 When considering a ‘teamwork’ approach to maximize drug safety, name at least five different ‘individuals’ with a key role in this drug safety process for a given patient. (Pg. 17)

Q2.2 How are the ‘standards of care’ for drug therapy monitoring determined? (Pg. 13)

Q2.8 What are the most important common clinical scenarios which require more frequent (compared with normal monitoring frequencies) laboratory monitoring? (Pg. 18)

Q2.3 What are several of the typical characteristics of the most worrisome adverse effects to systemic drug therapy (Pg. 13) Q2.4 In general, what are the most important issues to discuss with a patient before initiating systemic drug therapy which has a significant element of risk? (Pg. 14) Q2.5 What are three broad categories for mechanisms for drug interactions which can assist clinicians in anticipating important potential drug interactions? (Pg. 15) Q2.6 What are three to four examples of major drug risks ‘discovered’ many years after the drug’s release? (Pg. 15)

Introduction This chapter is unique in the context of the entire book. The principles that follow are a blend of science, literature reports, personal experience, and common sense. Rather than provide references for the principles and examples used in this chapter, the reader is encouraged to selectively pursue more detailed information and literature references pertaining to examples cited here in the various chapters devoted to the respective drug or drug category. Most of the examples provided deal with systemic drug therapy in dermatology, given that the systemic drugs commonly prescribed pose a significantly greater potential risk to the patient than topical or intralesional therapeutic options. Q2.1 Four words summarize the proactive approach to maximizing the safety of dermatologic drug therapy discussed in this chapter: anticipation, prevention, diagnosis, and management. The primary goals of maximizing drug safety are:

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Q2.9 What are some important examples of ‘thresholds of concern’ and ‘critical values’ for laboratory tests commonly used in drug monitoring (Table 2.1)? (Pg. 18) Q2.10 What are several important clinical strategies available for a specific abnormal lab value? (Pg. 18) Q2.11 In the event a potentially serious complication of drug therapy does occur, what are some of the most important management options available to clinicians? (Pg. 19)

1. Anticipation of which patients (comorbidities and other drugs the patient receives) and which drug regimens are at risk for various important adverse effects (AE); 2. Prevention of AE of potential concern by taking appropriate proactive safety measures; 3. Diagnosis at an early, reversible stage should an AE occur; and 4. Management of the AE in a safe and effective, and often collaborative, manner. I will present a number of general principles regarding how to maximize the safety and efficacy of systemic drug therapy. Each principle will be illustrated with several pertinent drug examples. Unlike many medical specialties, dermatologists in general must take greater precautions with systemic drug therapy, for the following reasons. Systemic drugs used in this field have typically been developed for specialties such as rheumatology, oncology, infectious diseases, and transplantation surgery. These specialties in general care for

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patients with more serious, possibly life-threatening, illnesses than the majority of conditions for which dermatologists prescribe the various systemic drugs. Clinicians in any field are obliged to avoid creating a greater risk with drug therapy than the innate risk (in that specific patient) of the underlying disease to be treated. This statement is the underlying principle behind the need for careful monitoring of systemic drug therapy in dermatology. It is essential to maximize the safety and minimize the risk of this drug therapy. How to optimally anticipate, prevent, diagnose, and manage specific drug AE to maximize drug safety is a central theme of this chapter and of the book as a whole. This is a broader viewpoint than merely ‘monitoring’ for AE. The goals of this broader approach are to (1) maximize overall drug safety for the patient, (2) improve the ‘emotional comfort’ of systemic drug therapy for the patient and physician, and (3) follow the appropriate ‘standards of care’ to minimize medicolegal risk. These overlapping goals are interdependent. For example, when appropriate standards of care are followed, the patient safety is the focus of these standards. In addition, when the patient’s safety and emotional comfort during drug therapy are truly of central importance to the physician, the medicolegal risk is negligible. This is particularly true if the patient assumes an active role in the decision making process for all aspects of any systemic drug therapy regimen, in turn forming a ‘therapeutic partnership’ with the prescribing physician. It is somewhat challenging to define the definitive sources of these so-called ‘standards of care.’ Q2.2 In general, such standards come from one or more of the following sources: 1. Specialty-based formal guidelines such as the American Academy of Dermatology ‘Guidelines of Care’; 2. Individual pharmaceutical company guidelines for specific drugs, such as the therapeutic guidelines and informed consent packet for isotretinoin (iPLEDGE) in women of childbearing potential; 3. The US Food and Drug Administration (FDA) Advisory Committee recommendations, such as those guidelines proposed in the early 1980s for monitoring the hematologic complications of dapsone; 4. Consensus conference publications, such as the consensus guidelines published in 2004 for isotretinoin therapy in acne patients; and 5. ‘Dear Health Care Professional’ letters (formerly ‘Dear Doctor’ letters) from pharmaceutical companies, with careful oversight by the FDA, updating physicians and other health care providers nationally regarding recent findings for specific AE. The reality is that the standards of care for a given drug are often a blend of several of these sources, with a certain amount of ambiguity as would be expected from such a mix. Historically, these standards of care were based on local practices in the ‘community’ in which the physician practiced. Currently the realities of the ‘information age’ in which we practice tend to create a trend towards national, if not global, standards of care. Such standards should be considered guidelines, and not mandates, with room for flexibility as the patient’s individual circumstances, clinician’s experience, and scientific ‘evidence’ justify. As far as possible, special efforts must always be made to ensure that the most serious adverse effects (SAE) ‘never’ occur. Q2.3 Characteristics of the most SAE given the highest priority in this chapter, and throughout the book, include at least several of the following: 1. a sudden, precipitous onset; 2. no early warning symptoms;

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3. no predictive laboratory tests; 4. potentially irreversible; and 5. a potentially serious outcome. Examples of such high-priority AE include (1) hematologic complications (pancytopenia from azathioprine or methotrexate, agranulocytosis from dapsone), (2) isotretinoin teratogenesis, (3) corticosteroid (CS) osteonecrosis, (4) opportunistic infections from tumor necrosis factor (TNF) inhibitors and other biologic therapeutics, and progressive multifocal leukoencephalopathy from rituximab and efalizumab (off the market). Principles to minimize the likelihood of these and other complications follow in the four major sections of this chapter. First, a few ‘baseline concepts.’ No matter how careful a physician may be, sooner or later ‘bad things’ will happen to a patient from drug therapy that he or she initiates. No medical risk reduction system is perfect, given the unpredictabilities of the human body. If the patient and physician can form a strong therapeutic partnership, and if the physician continues to work with the patient to promptly diagnose and manage any drug-induced complications, there can be a number of positive results: (1) the patient’s medical outcome is optimized, (2) the physician’s ethical obligations are met, and (3) the medicolegal risk is minimized. Nevertheless, the physician must take a ‘lifelong learner’ approach to any such unexpected complications, carefully analyzing the events leading to the specific drug complication, and learning how to minimize the likelihood of a similar therapeutic outcome in the future. On the following pages of this chapter, 33 ‘principles,’ with over 90 specific drug therapy examples, are used to illustrate the clinical approach for maximizing the safety of dermatologic drug therapy.

Anticipation This section is broken down into five subsections: (1) patient selection, (2) patient education, (3) baseline laboratory and related tests, (4) concomitant drug therapy—drug interactions, and (5) evolving guidelines—risk factors.

Patient Selection Principle #1. Carefully compare the ‘risk’ of the disease to be treated with the ‘risk’ of the drug regimen planned (in that particular patient); thus a ‘risk–risk’ assessment: • The risk of high-dose systemic CS in severe pemphigus vulgaris versus the risk from the same CS regimen in patients with either pemphigus foliaceus or localized epidermolysis bullosa acquisita. • The risk of 6 to 12 months of cyclosporine for a patient with limited plaque-type psoriasis versus the risk of the same regimen in a patient with debilitating and extensive pyoderma gangrenosum. • The risk of 1 to 2 weeks of cyclosporine for a patient with Stevens-Johnson syndrome versus the risk of burn unit therapy. • The risk of an interleukin IL-17 or IL-23 inhibitor in a patient with severe psoriasis with components of metabolic syndrome versus therapy with methotrexate or cyclosporine. Principle #2. Choose patients who can comprehend and com-

ply with important instructions for preventing and monitoring the most serious potential complications of systemic drug therapy. Examples in which this principle is most important include the following:

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• Th e importance of avoiding abrupt cessation of long-term, high-dose prednisone therapy—risk of hypothalamo-pituitary axis (HPA) complications such as an addisonian crisis. • The pregnancy prevention measures which are of central importance in isotretinoin therapy for women of childbearing potential. • The importance of avoiding significant amounts of alcohol with long-term methotrexate therapy for severe psoriasis or in women of childbearing potential on long-term acitretin therapy for psoriasis. Principle #3. All patients are not ‘created equal’ regarding the risk

for various AE. Examples of patients at significantly increased risk for the following AE (beyond the specifics of the drug regimen) include: • Methotrexate hepatotoxicity: obesity, alcohol abuse, diabetes mellitus, renal insufficiency. • CS osteoporosis: postmenopausal women, especially those who are thin and inactive. • CS osteonecrosis: recent significant local trauma, alcohol abuse, cigarette smoking, and presence of underlying hypercoagulable conditions. • TNF inhibitor use in patients with a personal or family history of multiple sclerosis. The bottom line is that individual patients must be carefully ‘matched’ with the safest and most effective drug regimen for the unique presentation of their dermatosis. This ‘match’ hinges on the various risk factors and demographic variables with which a specific patient presents. Perhaps the best example is the lesson provided by the specialty of rheumatology regarding the apparent lesser risk of methotrexate in rheumatoid arthritis (RA) patients compared with the historical risk of the same methotrexate therapy in psoriasis patients. This risk reduction was accomplished by (1) more careful patient selection of patients by rheumatologists, and (2) by the much lower risk of ‘metabolic syndrome’ in RA patients than in psoriasis patients.

Patient Education The multiple variables regarding a given course of systemic drug therapy are often very difficult for physicians to master. Thus, it should come as no surprise that the specific drug regimens and risks of these various therapies discussed are much more difficult for patients (who typically lack medical training) to understand. Q2.4 The patient needs to understand at least the following information: (1) how to take the medication, specifically the correct dose and timing, (2) the expected AE, (3) what symptoms to report, and (4) the specific monitoring using laboratory and related diagnostic tests. Particularly when significant risks to important organs or body systems are discussed, the understandable emotional reaction of most patients makes long-term retention very difficult. The above points and other concepts form the basis of the following principles. Principle #4. Careful and reasonably thorough patient education is essential to truly ‘informed consent’ (see Chapter 68): • Patients need to be active participants in therapeutic decisionmaking, which requires physicians to present the information in an understandable fashion. • In addition, the patient must be provided the opportunity to ask questions and be given adequate time to consider the therapeutic options presented. • The ‘perpetual’ question of what risks need to be discussed during informed consent always needs to be carefully considered;

what would a ‘reasonable patient’ want to know as a rough guide. Principle #5. Use patient handouts, written at a very under-

standable level, to reinforce important information and instructions concerning the drug therapy chosen: • The physician must emphasize the key information contained in the handout, but handouts are never a substitute for appropriate physician-patient communication. • The patient should be instructed to notify the physician if there are any questions pertinent to the handout provided. • The patient should be instructed to report any significant new symptoms that may develop subsequently (even if they are not sure these symptoms are attributed to the specific drug). • Sources for these handouts include National Psoriasis Foundation (major systemic therapies for psoriasis, including biologics), various pharmaceutical companies (acitretin/Soriatane), the American Medical Association (CS and many others), and various online sources. Consider creating your own personalized patient education handouts regarding specific drugs you commonly prescribe. Principle #6. Educate your patients regarding groups or clus-

ters of symptoms, which together are important for the detection of potentially serious drug-induced complications. The grouping of these symptoms may not be emphasized in the above-mentioned handouts: • CS osteonecrosis: focal, significant joint pain (especially hip, knee, shoulder) with decreased range of motion of the affected joint. • Isotretinoin pseudotumor cerebri: headache, visual change, nausea, and vomiting. • All current biologic therapeutics and opportunistic infections: fever plus localizing symptoms such as a cough. • Dapsone (or minocycline) hypersensitivity syndrome (DRESS): fever, fatigue, sore throat, adenopathy, and morbilliform eruption. A ‘two-way street’ of open communication between patient and physician is essential in maximizing the safety of systemic drug therapy. Any extra time the physician spends in this communication process should pay great dividends with regard to improved therapeutic outcomes.

Baseline Laboratory and Related Tests Any organ system with potential for drug-induced complications requires a baseline evaluation before initiating therapy. There are very few exceptions to this principle. It stands to reason that existing pathology in an organ system, for which a given drug has the potential to induce abnormalities, will increase the likelihood of further injury to this organ system. Principle #7. Assess the baseline status of any potential target organ or site of excretion for a given drug. Similarly, if a drug can induce a metabolic abnormality, check for baseline presence of this metabolic defect if such testing is currently available: • Baseline liver function tests and hepatitis viral serology: methotrexate hepatotoxicity (methotrexate ‘target’ organ) and with the full spectrum of biologics. • Baseline renal function assessment; at least testing serum creatinine, and possibly creatinine clearance: methotrexate hepatotoxicity or pancytopenia (site of methotrexate excretion). • Baseline (at least in the first month) comprehensive eye examination, including visual fields, in patients to receive hydroxychloroquine therapy.

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• B aseline testing for hyperglycemia or hyperlipidemia: prednisone therapy (metabolic abnormalities aggravated by prednisone). • Baseline testing for latent tuberculosis for all biologic therapeutics regardless of the indication. The choice of tuberculosis testing method (tuberculin test or interferon-γ release assay such as T-spot TB or Quantiferon Gold) is not yet fully clarified. Principle #8. Use the most optimal tests that predict which

patients are at increased risk for a specific AE. Typically such tests are ordered only at baseline. (Ideally many more of these predictive tests will be available in the future.): • Baseline glucose-6-phosphate dehydrogenase (G6PD) level: predicts magnitude of risk for dapsone hemolysis. (This test does not predict which patients are at risk for dapsone agranulocytosis or dapsone hypersensitivity syndrome.) • Baseline thiopurine methyltransferase level: predicts risk for azathioprine hematologic complications as well as guiding optimal azathioprine dosing. (This test does not predict azathioprine hepatotoxicity or hypersensitivity syndrome reactions.) There are a few select tests for which a baseline determination is not required. Near the end of long-term high-dose prednisone therapy, a morning cortisol determination (usually ∼8:30 AM) may be of value in assessing HPA function; a baseline determination is virtually never indicated. Some tests may require a delayed baseline determination. I formerly requested a ‘delayed baseline’ ultrasound-guided liver biopsy for methotrexate patients after 6 to 12 months of therapy, once it is clear that the patient tolerates the drug, benefits from the drug, and requires long-term methotrexate therapy. In current practice, a fibroscan after 6 to 12 months of therapy is appropriate. Still, overall the general rule holds: if you plan on monitoring a specific test during therapy with a given systemic drug, it is prudent to determine the baseline status of that specific test.

Concomitant Drug Therapy—Drug Interactions Chapter 66 is devoted entirely to the subject of drug interactions of importance to the dermatologist and other physicians using similar medications. However, a few principles must still be addressed in this setting. The vast majority of drug interactions can be anticipated, and thus prevented. Truly life-threatening drug interactions are quite uncommon and virtually always have been well publicized. Q2.5 The following are principles dealing with three categories of drug interactions of central importance to maximizing the safety of systemic drug therapy. Principle #9. Anticipate (and avoid) drug combinations that have overlapping target organs of potential toxicity: • Tetracycline or minocycline plus isotretinoin: pseudotumor cerebri. • Hydroxychloroquine plus chloroquine: antimalarial retinopathy. (It is acceptable practice to combine quinacrine with either of these two drugs, as quinacrine alone does not induce a retinopathy.) • Methotrexate and a second-generation retinoid (previously etretinate, now acitretin): probably an increased risk for hepatotoxicity. Principle #10. Anticipate interactions involving two drugs that

alter the same metabolic pathway: • Methotrexate and trimethoprim/sulfamethoxazole: increased risk for pancytopenia, given that these drugs inhibit folate metabolism.

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• A zathioprine and allopurinol or febuxostat: increased risk for hematologic complications, as these drugs affect parallel purine metabolic pathways. Principle #11. Anticipate (and avoid) drug combinations metab-

olized by the same cytochrome P-450 (CYP) pathway, particularly if there is a narrow therapeutic index for one of the drugs involved: • Rifampin (CYP3A4 enzyme inducer) plus hormonal contraceptives: loss of efficacy of the contraceptive with the potential for an unintended pregnancy. • Ketoconazole or erythromycin (CYP3A4 enzyme inhibitors) plus cyclosporine: increased risk for renal toxicity because of increased cyclosporine blood levels. This area of medicine is very complicated and it is very difficult to stay ‘current’ (see Chapter 66). At times, recently released drugs have important, potentially life-threatening interactions which are discovered only years later. The potential for torsades de pointes with life-threatening cardiac arrhythmias from terfenadine, astemizole, or cisapride (elucidated several years after the drugs’ release) in the presence of certain CYP enzyme inhibitors illustrates this point. Do your best to stay current: liberally use the numerous electronic resources for information on drug interactions. As a backup, use of your hospital’s drug information pharmacists is highly recommended to more effectively deal with this challenging area of medicine.

Evolving Guidelines—Risk Factors Typically, with the passage of time the magnitude of risk for various systemic drugs becomes clarified. The level of concern can go in one of two directions: over time there is either increased concern or decreased concern about various risks subsequent upon the publication of new data. Furthermore, specific new risk factors can be elucidated as new scientific information is reported. Principle #12. Q2.6 Certain risks or risk factors for systemic

therapies may be discovered many years after a specific drug is released. It is imperative to ‘stay tuned’ regarding standards of care, as discussed in the Introduction: • Psoralen and Ultraviolet A (PUVA) therapy: an increased risk for squamous cell carcinoma of the male genitalia (specific risk factor—male gender, without clothing protection for the groin region during PUVA treatments). • PUVA-induced melanoma: probably an increased risk in patients receiving more than 250 to 350 treatments over a lifetime (specific risk factor—very large number of PUVA treatments). • Minocycline drug reaction with eosinophils and systemic symptoms (DRESS) or minocycline-induced lupus erythematosus: the magnitude of risk for these complications was not clarified until over a decade after the drug’s release. • Ketoconazole hepatotoxicity: magnitude of risk overall and potential for fatal outcomes were not clarified until several years after the drug’s release. • Boxed warnings for tumor necrosis factor (TNF) inhibitors concerning ‘opportunistic’ (bacterial, fungal, and parasitic) infections were expanded in the package insert many years after the drugs’ release. Principle #13. In contrast, the perceived magnitude of risk for a particular AE may decrease over time as new scientific evidence accumulates: • Antimalarial retinopathy: markedly lower risk than originally perceived, largely because of more careful antimalarial dosing schemes, and perhaps also to greater use of hydroxychloroquine rather than chloroquine.

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Introduction

• P UVA cataracts: primarily a risk in patients who fail to comply with current regimens regarding Ultraviolet A (UVA)-protective wraparound sunglasses. • Prednisone bursts and osteonecrosis risk: although this issue is still cloudy in the legal system, the scientific evidence ‘rules against’ there being a true risk of this bone complication with short courses (‘bursts’) of systemic CS. Principle #14. In many clinical scenarios, physicians must make decisions about measures to prevent important potential drug risks before all necessary information is published concerning whether there truly is an increased risk of a specific complication: • TNF inhibitors (etanercept, adalimumab, infliximab, certolizumab) and IL-12/23, IL-17, and IL-23 inhibitors tuberculosis (TB) risk: at least order a baseline purified protein derivative (PPD) or interferon-γ release assay such as T-spot TB (and selectively order a chest x-ray in higher-risk patients or in positivity with the above tests) before initiating therapy. • TNF inhibitors (etanercept, adalimumab, infliximab, certolizumab) and risk of demyelinating diseases: at least check personal and family history closely for multiple sclerosis and related demyelinating disorders before initiating therapy. • Isotretinoin, apremilast, and brodalumab risk of suicide; in each case all three drugs may at least induce severe depression if patient baseline depression is present (even if population studies do not show a direct connection with these drugs and suicide). Avoid these drugs when moderate-severe depression (or a history of same) is present. As challenging as it may be, physicians are obliged to stay ‘current’ with the latest published information on the magnitude of risk from the drugs we use. Truly important ‘new risks’ tend to be widely and repeatedly disseminated to physicians, with the socalled ‘Dear Health Care Professional’ letters from the FDA being a common vehicle for the dissemination of such information.

Prevention This section of the chapter will be divided into three subsections as follows: (1) patient measures to reduce risks, (2) therapeutic interventions to minimize drug risk, and (3) timing of risk and medication errors.

Patient Measures to Reduce Risks Principle #15. Patients should take all reasonable protective measures to prevent important AE: • Prevention of squamous cell carcinoma of male genitalia caused by PUVA therapy: wearing a ‘jockstrap’ or underwear during a PUVA treatment. • Prevention of cataracts in PUVA therapy: wearing opaque goggles during the PUVA treatment and wearing wraparound UVA-protective sunglasses when exposed to outdoor light, at least until sundown the day of the PUVA treatment.

Therapeutic Interventions to Minimize Drug Risk There are many occasions in which the patient would benefit from a specific systemic drug, yet there are worrisome risk factors for a given AE. If the drug regimen is essential for the patient, concomitant medical therapy to reduce the negative impact of the AE is logical and appropriate in most cases.

Principle #16. Use all reasonable adjunctive therapeutic mea-

sures to minimize the risk of various AE: • Daily folic acid therapy in patients receiving methotrexate: prevention of gastrointestinal (GI) AE and minimization of pancytopenia risk. (Ideally, folic acid should be used in all methotrexate patients; the benefits easily outweigh the theoretical risk of loss of efficacy in psoriasis.) • Calcium, vitamin D, and possibly estrogens, bisphosphonates, PTH analogs or nasal calcitonin: use in patients receiving longterm systemic CS therapy at or above physiologic doses. (Use a greater number of these preventative therapies in higher-risk patients.)

Timing of Risk and Medication Errors The prevention of many AE requires either heightened awareness with more frequent monitoring (drugs with a specific timing of greatest risk) or careful patient education (for potentially serious medication errors). In either setting a proactive physician style is preferred to maximize safety. Principle #17. For the most potentially SAE of systemic drugs, learn the timing of greatest risk for the drug-induced complication while monitoring the patient most carefully during this period: • Dapsone agranulocytosis or dapsone-induced DRESS is primarily an issue between weeks 3 and 12 of therapy. (Minocycline-induced DRESS: timing of greatest risk is roughly in the same interval, particularly in the first 2 months of therapy.) • Methotrexate or azathioprine pancytopenia: the risk is greatest primarily in the first 4 to 6 weeks of therapy, unless a drug interaction is a precipitating factor later in the course of therapy. • Prednisone osteonecrosis: the risk begins to increase substantially by months 2 to 3 of pharmacologic dose CS therapy. (This risk tends to parallel the overall development of cushingoid changes in the patient.) • Timing of rituximab-induced expected CD20 marked reduction and recovery in pemphigus vulgaris therapy; the recovery may help determine the optimal timing of a subsequent rituximab course. Principle #18. Medication errors are largely preventable with

careful patient education and, if necessary, cross-checks on potentially unreliable patients. These medication errors can be caused by either dose omissions or dose duplications: • Methotrexate weekly dosing scheme: the literature has many reports of pancytopenia caused by inadvertent daily dosing of methotrexate. If necessary, another caregiver or family member should place the drug in the slot for just one specific day each week in a weekly pill container, particularly for older patients. • Hormonal contraceptives and isotretinoin or thalidomide: pregnancy prevention is critical in women of childbearing potential. Omission of oral contraceptives for even a day can lead to unintended pregnancy in women of childbearing potential prescribed these potent teratogens.

Diagnosis This section is divided into five subsections as follows: (1) evolving guidelines for monitoring, (2) a teamwork approach for maximizing the safety of drug therapy, (3) use of the most optimal diagnostic tests, (4) higher-risk scenarios, and (5) efficient and thorough record keeping.

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Evolving Guidelines for Monitoring As discussed under the section ‘Anticipation’, newer scientific evidence commonly leads to new or revised guidelines for standards of care. As before, the level of concern can increase or decrease over time with the release of this new scientific information. Principle #19. Stay current with changing guidelines for diag-

nosing important complications of systemic drug therapy at an early, reversible stage: • Methotrexate chest x-rays for pneumonitis: pneumonitis from methotrexate is a significant risk in RA patients. In contrast, the negligible risk for this complication in psoriasis patients led to elimination of a previous yearly requirement for chest X-rays in more recent methotrexate guidelines. • TNF inhibitors (etanercept, adalimumab, infliximab, certolizumab) and subsequent biologics and tuberculin skin test or interferon-γ releasing assay (IGRA): the somewhat recent overall resurgence in incidence of TB and the TNF-α role in stabilizing granulomatous responses leads to this guideline for screening patients for TB before initiating therapy. • There is inconsistent package insert requirements for follow-up of latent TB screening for all four subgroups of biologics for moderate-severe psoriasis. A significant number of clinicians (including myself) have adopted yearly latent TB screening for all biologic therapeutics (and most oral immunosuppressive agents).

A Teamwork Approach for Maximizing the Safety of Drug Therapy

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• F ull skin examination for PUVA/NB-UVB (narrow-band ultraviolet B) or patients on systemic immunosuppressive therapy: detection of melanoma, squamous cell carcinoma, and basal cell carcinoma (and precursors thereof ). • Neurologic examination (screening style) for dapsone motor neuropathy or thalidomide sensory neuropathy: screening done by the prescribing physician, possibly verified by a consultant. • Morbilliform eruption and related DRESS syndrome findings caused by dapsone, minocycline, or azathioprine: reported by the patient but verified by the prescribing physician. Principle #22. Comanagement with another consultant is com-

monly an essential part of this ‘teamwork’ approach to maximizing the safety of systemic drug therapy: • Gastroenterologist: for recent trend of using fibroscans in detection of fatty liver or fibrosis in long-term methotrexate therapy. • Ophthalmologist: integral part of monitoring guidelines for PUVA and antimalarial therapy. • Primary physician: for management decisions regarding elevated blood glucose or blood pressure with CS therapy or for management of hyperlipidemia in patients on long-term systemic retinoid or cyclosporine therapy.

Use of Optimal Diagnostic Tests

Despite recent trends in managed care to fragment care and limit access to various medical specialties in the name of cost savings, a teamwork approach for risk reduction is imperative. Q2.7 A ‘team’ consisting of the prescribing physician, the patient (including their family), and, in many cases, the patient’s primary physician or another specialist, is of central importance. In addition, pharmacists and members of the physician’s office staff have key roles in this team. Each member of the team has an important role in maximizing the safety of systemic drug therapy.

Principle #23. Stay current regarding optimal diagnostic tests that have improved sensitivity and precision for early diagnosis of important AE at a reversible stage: • CS osteonecrosis diagnosis: magnetic resonance imaging is far superior to conventional X-rays for early diagnosis, and can allow timely performance of core decompression to salvage the affected bone or joint. • CS osteoporosis diagnosis: dual-energy X-ray absorptiometry (Dexascan) has much greater sensitivity than conventional X-rays for early recognition of bone density loss. • Methotrexate hepatotoxicity diagnosis: as discussed previously with fibroscan largely replacing ultrasound-guided liver biopsies.

Principle #20. In addition to the importance of patient aware-

Principle #24. Realize that many diagnostic tests provide com-

ness of reporting symptoms suggesting the early phases of selected complications, the patient often has a role in home monitoring for selected complications: • Cyclosporine or CS and hypertension: with a growing number of patients using home blood pressure cuffs or electronic blood pressure monitoring devices, this is a relatively easy area of home surveillance for AE. The patient merely needs to be told what levels of blood pressure elevation should be reported to the prescribing physician and/or primary physician. • CS and home glucose monitoring: even though the history of diabetes mellitus should lead to careful scrutiny regarding the appropriateness of systemic CS, there are many circumstances in which prednisone therapy is essential in diabetic patients. Home glucose monitoring provides for relatively easy surveillance and follow-up. • CS and weight gain: the simple bathroom scale can provide useful information on the progression of cushingoid changes or for signs of increasing fluid overload in patients with previously well-compensated congestive heart failure. Principle #21. The prescribing physician’s examination is essen-

tial for detection or verification of important early signs of various drug complications:

plementary information for the clinician: • Transaminase values and liver histology for methotrexate hepatotoxicity: one method of testing (transaminases) assesses hepatocellular toxicity, whereas the other method (liver biopsy/ histology) assesses the potential for slow progression from fatty liver changes to focal fibrosis to cirrhosis; both tests in combination are essential for proper hepatic monitoring. • Ordering both transaminases (SGOT/AST and SGPT/ALT) for detection of dapsone, azathioprine, and methotrexate hepatotoxicity: improved sensitivity and specificity when ordering both tests; subsequently, tests for hepatobiliary obstruction (bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase) can be useful adjuncts if significant transaminase elevation has already occurred.

Higher-Risk Scenarios As discussed earlier, patients are not ‘all created equal’ when it comes to risk factors for AE from systemic drug therapy. The more a physician knows about relatively high-risk clinical scenarios (with corresponding increased surveillance for AE in these settings), the more that physician can maximize the safety of the drug therapy in that particular patient.

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Principle #25. Q2.8 Laboratory monitoring and related diagnostic tests should be performed more frequently with (1) higher-risk patients, (2) abnormal test results, and (3) at high-risk periods—typically early in therapy: Principle #26. Q2.9 Become familiar with ‘thresholds of concern’ (levels at which to consider dose reduction and/or more frequent monitoring) and ‘critical values’ (levels at which therapy should be stopped, possibly indefinitely) for various laboratory tests and related monitoring procedures (Table 2.1): Q2.10 It is of tremendous importance for the reader to realize that the test result ranges in Table 2.1 are merely rough guidelines for clinicians to use. The rapidity of change and the overall trend of the laboratory values are of at least equal importance to recognize. Regardless of the actual laboratory test abnormality or the rapidity of change, the clinician should be mindful of four possible options (depending on the clinical circumstances in an individual patient): 1. Discontinue the drug therapy temporarily or indefinitely; 2. Reduce the drug dose; 3. Increase the frequency of test monitoring; and 4. Treat the AE while carefully continuing the therapy. These are not mutually exclusive options: generally, several of the above steps are instituted simultaneously. Again, the key is to know which circumstances constitute a high-risk clinical scenario, and subsequently to proceed therapeutically with greater caution in these clinical settings.

Efficient and Thorough Record Keeping It is quite difficult to stay ‘current’ regarding scientific advancements related to drug safety in dermatologic therapeutics. It is at least an equal challenge to keep track of the following aspects of medical record keeping for the five general steps of maximizing safety presented in this chapter. The issues here include (to name a few): 1. Documenting informed consent discussions;

2. The changing frequency of laboratory tests any given patient should have, depending on the stage of therapy and the dose of the drug; 3. Keeping track of which patients did not have laboratory tests performed when scheduled; 4. Notifying patients about laboratory test results, particularly abnormal results, and the resultant algorithm describing how to respond to these abnormal results; and 5. How to efficiently document steps 2 through 4 above. What is a busy clinician to do? Fortunately, the electronic/information era in which we practice has provided some solutions. I previously kept written test result flow sheets on patients I followed in the 1980s, but through the 1990s and into the 21st century most laboratories are capable of printing (or simply displaying) computer-generated flow sheets of test results. Similarly, most electronic medical records (EMR) can provide a summary of test results over time. If a clinician can readily find the last 2 to 3 sets of test results, most decision making proceeds without much difficulty. There should be a cross-check system regarding missed appointments and missed laboratory tests for patients on systemic drug therapy. I personally believe this is an area of potential medicolegal risk. In general, it is helpful to have a patient call about test results (in a specified time frame) if not previously notified about test results by mail or a phone call from the physician’s office. A less time-consuming step is a policy that only severely abnormal test results require phone notification of the patient; otherwise communication with a letter is sufficient. The reality is that even with normal test results, the physician (or physician’s staff) must commonly contact the patient about drug dose changes, and hence the need to document and to communicate this decision. A few principles need to be listed, some of which overlap with other chapters (such as Chapter 68 Informed Consent and Risk Management). Principle #27. An important medicolegal dictum states that ‘if

Threshold of concern

Critical value

it was not written, it was not done.’ An individual physician needs to find a balance of thoroughness and efficiency. Personally, I believe that dictated chart notes more readily allow this optimal balance—I believe voice recognition software is the most efficient manner of documenting important informed consent discussions:

WBC count (#/mm3)

erythromycin), except MRSA and enterococcus Clarithromycin and azithromycin → GN and atypical mycobacterial coverage (see text)

Modification of drug target via methylation of rRNA nucleotides or mutation of ribosomal components Decreasing intrabacterial accumulation via drug efflux pump

Renal: erythromycin and clarithromycin Hepatic: azithromycin

B

Fluoroquinolones

Interfere with bacterial DNA replication via inhibition of DNA gyrase (bacterial topopisomerase II) +/- topoisomerase IV

GP (target is topoisomerase IV) and GN (target is DNA gyrase) First- and second-generation quinolones (ciprofloxacin, ofloxacin and nalidixic acid) only target DNA gyrase → only effective against GN organisms Third and fourth generation quinolones (levofloxacin, moxifloxacin, sparfloxacin and gatifloxacin) target both topoisomerase forms (IV>II) → increased GP coverage, but decreased GN coverage Ciprofloxacin, ofloxacin and levofloxacin have some activity against atypical mycobacteria

Alteration of drug target mechanism Decreasing intrabacterial accumulation via drug efflux pump

Renal, except moxifloxacin

C

Tetracyclines

Bind to 30s subunit of bacterial ribosome, inhibiting RNAdependent protein synthesis Anti-inflammatory properties (see text)

Various GP and GN skin infections, including MRSA and those caused by Chlamydia spp., Rickettsia spp., Mycoplasma spp., atypical mycobacteria, spirochetes and Lyme disease

Decreasing intrabacterial accumulation via decreasing influx or increasing efflux Alteration of drug target (see text)

Renal, except doxycycline (mainly via GI tract)

D

Rifamycins

Bind to β-subunit of bacterial DNA-dependent RNA polymerase, inhibiting RNA and protein synthesis

Various mycobacteria (M. tuberculosis, M. leprae, M. marinum) and some other GP (staphylococcus) and GN organisms

Alteration of drug target (see text)

Hepatic

C

Trimethoprim- Sulfamethoxazole

Dihydrofolate reductase inhibitor (trimethoprim) and dihydropteroate synthetase inhibitor (sulfamethoxazole) → decreased tetrahydrofolic acid → decreased bacterial nucleic acid and protein synthesis

Various GP cocci (MRSA, Enterococcus faecalis and S. pyogenes), H. influenzae, Pneumocystis jirovecii, Nocardia spp., Chlamydia, and various GN

Alteration of drug target via acquired mutations and/or plasmid acquisition Decreasing intrabacterial accumulation via active drug efflux Auxotrophic bacteria (naturally resistant)

Hepatic, Renal

D

Clindamycin

Binds to 50S subunit of bacterial ribosomal RNA → decreased ribosomal translocation and protein synthesis

GP cocci (Staphylococcus spp. and Streptococcus spp.) and anaerobes (Bacteroides spp. and Clostridium perfringens), but not usually GN (except Capnocytophaga canimorsus)

Alteration of drug target via acquired mutations and/ or plasmid acquisition (see text) Auxotrophic bacteria (naturally resistant)

Hepatic

B

For those with renal excretion, dose adjustment needed in context of renal failure. CNS, Central nervous system; DNA, deoxyribonucleic acid; GI, gastrointestinal; GP, gram-positive; GN, gram-negative; hVISA, heteroresistant vancomycin-intermediate S. aureus; IV, intravenous; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-sensitive S. aureus; RNA, ribonucleic acid; rRNA, ribosomal RNA; USSTI, uncomplicated skin and soft tissue infection; VISA, vancomycin-intermediate S. aureus; VRSA, vancomycin-resistant S. aureus.

Systemic Drugs for Infectious Diseases

Mechanism of Action

PART III

Pregnancy Category

Drug

CHAPTER 9

Each of these functions serves to initiate bacterial cell lysis and death.12 Antimicrobial Activity. Both penicillin G and penicillin V are categorized as natural first-generation penicillins. The semisynthethic first-generation penicillins (isoxazolylpenicillins) are characterized by their penicillinase resistance. First-generation penicillins share a similar antimicrobial spectrum against Grampositive cocci and rods, Gram-negative cocci, and anaerobes (see Table 9.1). Second-generation agents (aminopenicillins) exhibit expanded coverage to include inhibition of Gram-negative bacilli. Third generation extended-spectrum penicillins (carboxypenicillins) and the fourth-generation penicillins (ureidopenicillins) are both parenteral and exhibit antipseudomonal activity, especially when combined with an aminoglycoside antibiotic.12 Only oral antibacterial agents will be discussed in this chapter. Pharmacokinetics. Q9.2 Penicillin absorption upon oral administration differs depending on each agents’ acid stability and binding onto food. Gastrointestinal (GI) absorption can be optimized by administration 1 hour before or after a meal.12 The elimination half-lives for most penicillins are short (14 days is required for resolution of MRSA folliculitis Maximum daily dose = 12 g Maximum daily dose = 1 g Maximum single dose = 600 mg; Should never be used as monotherapy (see text) Maximum daily dose: 2–4 g; second-line therapy or if evidence of MRSA Maximum daily dose: 4 g; second-line therapy Note: infant/children doses reported515

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Systemic Antibacterial Agents

75

TABLE Antimicrobial Therapy for Staphylococcal and Streptococcal Infections of Dermatologic Significance—cont’d 9.2

Disease Entity

Antibiotic

Adult Dosage

Comments

Scarlet Fever

Penicillin V

500 mg BID to TID PO

Amoxicillin Cephalexin Azithromycin Clindamycin

500 mg BID PO 500 mg BID PO 500 mg PO × 1 followed by 250 mg PO on days 2–5 300 mg TID PO

Treatment of choice for GAS pharyngitis; should be administered within first 48 hours of illness and treated for 10 days to reduce risk of acute glomerulonephritis and rheumatic fever Used in penicillin-allergic patients

Penicillin Amoxicillin

500 mg every 6 h PO 875 mg BID PO

Cephalexin Clindamycin TMP-SMX

500 mg QID PO 300 to 450 mg QID PO 1 to 2 double strength tablets BID PO

Erysipelas

Used in penicillin-allergic patients and if concern for macrolide resistance Duration of treatment: 5–14 days Note: if systemic symptoms, inability to tolerate PO, or progression on oral therapy, parenteral treatment is warranted13 Used in penicillin-allergic patients Used in penicillin-allergic patients Used in penicillin-allergic patients

BID, Twice a day; GAS, group A streptococcus; IV, intravenous; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive S. aureus; PO, per os = oral; QID, 4 times a day; SSTI, skin and soft tissue infection; TID, 3 times a day; TMP-SMX, trimethoprim-sulfamethoxazole.

• BOX 9.1

Drug Risks Profile—Penicillins

Contraindications Hypersensitivity to penicillins or other beta-lactam antibiotics

Primarily an issue with anaphylaxis, SJS/TEN

Boxed Warnings None related to oral formulations

Warnings & Precautionsa Hypersensitivity

Gi

aUrticaria/angioedema

Cholestatic jaundice with amox/ clavulanate Diarrhea more often with amox/ clavulanate than amox alone

SJS/TEN rarely (predominantly IV forms) aPotential cross-reaction with cephalosporins and other beta-lactam antibiotics (see text)

Infections EBV infections in combination with ampicillin exanthem

Pregnancy Prescribing Status Traditional US Food and Drug Administration rating—category C

Newer ratingb—compatible

aUnder “Warnings

& Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid. bSee Chapter 65, Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings. Amox, Amoxicillin; EBV, epstein-Barr virus; GI, gastrointestinal; IV, intravenous; SJS/TEN, Stevens– Johnson syndrome/toxic epidermal necrolysis. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https:// www.wolterskluwercdi.com/facts-comparisons-online/).

Cephalosporins Cephalexin and Many Others Most cephalosporins are antibiotics produced and derived as byproducts of the mold Cephalosporium acremonium. Cephalosporins have a basic structural core consisting of a 4-membered

β-lactam ring attached to a 6-membered dihydrothiazine ring, and therefore are β-lactams. The two-ring combination gives the cephalosporin structure inherent resistance to β-lactamase enzymes, as compared with penicillins, which are composed of a 5-membered thiazolidine ring.23 Most cephalosporins are considered safe in children. Cephalosporins are generally pregnancy category B, with a low likelihood of congenital malformations when used during the second and third trimesters.4 Caution is suggested in women who are breastfeeding, as the small quantities of cephalosporins in breast milk have been associated with reports of diarrhea, candidal infections, and skin eruptions in nursing infants.24

Pharmacology Mechanism of Action (See Penicillins) Antimicrobial Activity. The cephalosporins have been grouped

into ‘generations’ based on their general spectrum of antimicrobial activity. There are five generations of cephalosporins. Table 9.1 reviews the common agents in each generation and their antimicrobial spectrums. Future Directions. A second fifth-generation cephalosporin, ceftobiprole is under consideration for US Food and Drug Administration (FDA) approval for treatment of complicated skin and soft tissue infection (CSSTI).25,26 Ceftobiprole has shown activity against methicillin-resistant S. aureus (MRSA), in addition to Streptococcus pneumoniae, Pseudomonas spp., and enterococci.27,28 A new antipseudomonal cephalosporin, ceftolazone, has demonstrated activity against carbapenem-resistant and multidrugresistant Pseudomonas aeruginosa clinical strains.29 In addition, newer studies have demonstrated promising results with ceftolazone combined with tazobactam.30 Pharmacokinetics. The absorption properties of the currently available cephalosporins vary greatly, with peak serum concentrations dependent on administration in relation to food intake.23 Q9.2 Cefaclor, cefadroxil, and cephalexin are best absorbed from

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an empty stomach, whereas the bioavailability of cefuroxime is increased when taken with food.31 The half-life of most parenterally administered cephalosporins varies between 0.5 and 2 hours, although the 6 to 8 hour half-life of ceftriaxone permits once-daily dosing. Table 9.1 reviews the metabolism of cephalosporins.

Clinical Use

special uses of individual cephalosporins include selected STD (i.e., gonorrhea), P. aeruginosa infections, including ecthyma gangrenosum, diabetic foot infections and Lyme disease.23 See Table 9.3 for list of cephalosporins classified by generation, and Table 9.2 for common dermatologic indications and dosage guidelines for cephalosporins.

Dermatologic Indications. Oral cephalosporins are used pri-

Adverse Effects Hypersensitivity Reactions and Cross-Reaction Potential.

marily in ambulatory dermatologic practice to treat uncomplicated skin and soft tissue infection (USSTI), such as impetigo, folliculitis, furuncles, carbuncles, acute bacterial paronychia, cellulitis, ecthyma, erysipelas, and postoperative wound infections. Severe infections, such as complicated cellulitis and necrotizing fasciitis require intravenous (IV) antibacterial agents.13,23,32 Additional

Hypersensitivity reactions, reported in only 1% to 3% of treated individuals, include cutaneous findings, such as urticaria, maculopapular eruptions, and pruritus (Box 9.2).23 The incidence of anaphylaxis secondary to cephalosporin administration is even more infrequent, estimated between 0.0001% to 0.1%.20 For discussion on potential cross-reactivity of cephalosporins

TABLE Currently Available US Food and Drug Administration-Approved Cephalosporins 9.3

Generic Namea

Trade Name(s)

Route

Pregnancy Category

Lactation Category

Adult Dose

First-Generation Cephalosporins Cefadroxil

Duricef

PO

B

S

500 mg BID to 1–2 g/day (QD or BID)

Cefazolin

Ancef

IM, IV

B

S

0.5–1.5 g every 6–8 hours

Cephalexin

Keflex, Panixine Disperdoseb

PO

B

U

250–500 mg 4 times daily

Second-Generation Cephalosporins Cefaclor

Ceclor

PO

B

U

250–500 mg 3 times daily

Cefprozil

Cefzil

PO

B

PS

250–500 mg a day (QD or BID)

Cefuroxime axetil

Ceftin

PO

B

PS

250–500 mg twice daily

Cefuroxime

Zinacef

IV/IM

B

PS

0.75–1.5 g every 6–8 hours

Cephamycins (second generation) Cefotetan

Cefotan

IM, IV

B

U

1–3 g every 12 hours

Cefoxitin

Mefoxin

IM, IV

B

S

1–2 g every 4–6 hours

Third-Generation Cephalosporins Cefixime

Suprax

PO

B

U

200 mg twice daily or 400 mg QID

Cefdinir

Omnicef

PO

B

PS

300 mg twice daily

Cefotaxime

Claforan

IM, IV

B

PS

1–2 g every 4–8 hours

Cefpodoxime

Vantin

PO

B

PS

100–400 mg twice daily

Ceftazidime

Fortaz, Tazicef

IM, IV

B

PS

0.5–2 g every 8–12 hours

Ceftibuten

Cedax

PO

B

U

400 mg once daily

Cefditorenc

Spectracef

PO

B

U

200–400 mg twice daily

Ceftriaxone

Rocephin

IM, IV

B

PS

0.5–2 g every 12–24 hours

IM, IV

B

U

1–2 g every 12 hours

IV

B

U

600 mg every 12 hours

Fourth-Generation Cephalosporins Cefepime

Maxipime

Fifth-Generation Cephalosporins Ceftaroline

Teflaro

For Lactation category: S, Safe; PS, Probably safe; PU, Possibly unsafe; U, Unknown. (Keflin), cephapirin (Cefadyl), cefmetazole (Zefazone), cephaloridine (Ceporin), cephradine (Velosef), loracarbef (Lorabid), cefoperazone (Cefobid) and ceftizoxime (Cefizox) are no longer available in the United States. bDispersible tablet formulation. cFor uncomplicated skin infections, cefditoren 200 mg BID has been used. BID, Twice a day; IM, intramuscular; IV, intravenous; PO, per os = oral; QD, every day.

aCephalothin

CHAPTER 9

with penicillins, see penicillin section. Q9.3 The cross-reactivity between penicillins and cephalosporins is related to the structural similarities of their individual side chain determinants.33–35 However, even when side chains are similar, cross-reactions are not guaranteed.36 Thus, careful skin testing with multiple β-lactam determinants should be performed in patients with history of β-lactam allergy who require penicillin or cephalosporin therapy.22 Other Adverse Effects. Q9.4 Box 9.2 summarizes the most important AE associated with cephalosporin administration. GI toxicities are relatively frequent with cephalosporin use, including nausea, vomiting, or diarrhea.23,32 Other potential AE include vaginal candidiasis, hematopoietic changes, mental and sleep disturbance, and transaminitis.37 Drug Interactions. Some of the most important drug interactions for cephalosporins include the following: 1. Cephalosporins (such as cefotetan), which contain a N-methyl thiotetrazole (NMMT) ring, may induce disulfiram-like reactions with alcohol ingestion.38 2. The NMMT ring inhibits production of vitamin-K clotting factors, resulting in prolongation of INR in patients on warfarin.21,39 3. Probenecid competes with renal tubular secretion of some cephalosporins, increasing and prolonging their plasma levels. 4. Some cephalosporins may increase the risk of nephrotoxicity, when coadministered with aminoglycosides or potent diuretics.21,40 5. The potential impact of oral antibiotics on the efficacy of oral contraceptives is reviewed under the ‘Drug Interactions’ sections for both TCNs and rifamycins. 6. Ceftaroline appears to exhibit minimal interaction with the cytochrome P-450 (CYP) system, although no studies on drug interaction have been performed with this newer cephalosporin.25,41 Dosage. Table 9.2 contains common dermatologic indications and dosage guidelines for cephalosporins. A single IM injection of ceftriaxone 1 g is an effective treatment for uncomplicated gonorrhea, (as are single oral doses of cefpodoxime and cefixime). For • BOX 9.2 Drug Risks Profile—Cephalosporins Contraindications Hypersensitivity to cephalosporins and related antibiotics

Boxed Warnings None listed

Warnings & Precautionsa Hypersensitivity Reactions

Infections

Cross-allergenicity to penicillins (see text) aSerum sickness like reactions (esp. cefaclor) with fever, arthralgias, arthritis, esp. with second course

aCDAD

(has been reported to occur 2 months after d/c rx)

Coagulation aMay

↑ INR in warfarin patients— nutritionally deficient patients, chronic therapy, liver and kidney disease

Pregnancy Prescribing Status Traditional US Food and Drug Administration rating—category B aUnder “Warnings

Newer rating b—compatible

& Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid. bSee Chapter 65, Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings. CDAD, Clostridium difficile-associated disease; INR, international normalized ratio. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https:// www.wolterskluwercdi.com/facts-comparisons-online/).

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77

ecthyma gangrenosum, treatment with IV ceftazidime 2 g every 8 hours is recommended; in the setting of immunosuppression or sepsis, multiagent antipseudomonal therapy is warranted.42

β-Lactam and β-Lactamase Inhibitor Combinations Amoxicillin/Clavulanate and Others β-lactamase enzymes render β-lactam antibiotics inactive by irreversibly hydrolyzing the amide bond of the β-lactam ring. The production of a β-lactamase is controlled by either chromosomal or plasmid genes, and these genetic capabilities may be transferred among bacteria.43 β-lactamase inhibitors, such as clavulanate, sulbactam, and tazobactam, when combined with a β-lactam antibiotic, inhibit β-lactamase produced by Enterobacteriaceae, S. aureus, and Gram-negative anaerobes,44 thereby restoring the spectrum activity of the β-lactams. Antibacterial Activity. Significant activity against β-lactamase produced by MSSA, Haemophilus spp, Klebsiella spp., Escherichia coli, Proteus spp., and Bacterioides fragilis has been noted. However, β-lactamase inhibitors do not inhibit β-lactamases produced by P. aeruginosa, Enterobacter, and Citrobacter spp.45 Pharmacokinetics. When clavulanate is given orally with amoxicillin (Amox/Clav), it is rapidly absorbed, with peak concentrations reached 40 to 60 minutes after ingestion, and bioavailability not significantly affected by food.45,46 Ampicillin–sulbactam (Amp/Sulb), ticarcillin–clavulanate (Ticar/Clav) and piperacillin–tazobactam (Pip/Tazo) are administered intravenously. These agents are subject to renal metabolism and warrant dose adjustment in renal insufficiency.

Clinical Use Dermatologic Indications. The broad-spectrum antimicrobial coverage provided by Amox/Clav, Amp/Sulb, Ticar/Clav, and Pip/ Tazo makes these agents useful for the treatment of polymicrobial infections. The recommended treatment for animal or human bites infected by combined aerobic and anaerobic pathogens is Amox/Clav.13,43 Ticar/Clav and Pip/Tazo exhibit an even broader antibacterial spectrum and are effective in treating CSSTI, such as diabetic foot ulcers, infected decubiti, and burn wounds.47,48 Adverse Effects. GI AE are most often associated with Amox/ Clav and Pip/Tazo, most commonly diarrhea.49 Diarrhea is less frequent when Amox/Clav is administered with food. Drug Interactions. When administered concomitantly with β-lactam/β-lactamase inhibitor combinations, oral probenecid slows the rate of renal tubular secretion of the β-lactam agent, resulting in an increase in serum concentration and delayed renal excretion.45,50 The potential impact on the efficacy of oral contraceptives is reviewed later under the ‘Drug Interactions’ sections for both TCNs and rifamycins. Dosage. Amox/clav is dosed at 875/125 mg twice daily.13

Other Systemic Antibacterials that Inhibit Cell Wall Synthesis Glycopeptides Vancomycin and teicoplanin inhibit bacterial cell wall synthesis by forming noncovalent complexes with precursors of

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bacterial peptidoglycan, a contrasting mechanism to that of the β-lactam agents.51

Pharmacology Antibacterial Activity. Vancomycin and teicoplanin inhibit a broad range of Gram-positive bacteria, including staphylococci, streptococci and most enterococci. Q9.5 Resistance to vancomycin is mediated by several mechanisms (see Table 9.1) and has resulted in the increased prevalence of vancomycin-resistant S. aureus (VRSA), vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant enterococci (VRE).52,53 Derived from vancomycin, the lipoglycopeptides, dalbavancin, oritavancin, and telovancin treat VRSA, VISA, and VRE.53 The recently described increasing minimal inhibitory concentration (termed MIC creep) of vancomycin is not uniform when analyzed across multiple centers.54 Pharmacokinetics. Vancomycin and teicoplanin are administered parenterally given their minimal intestinal absorption. As compared with vancomycin, teicoplanin has a longer half-life and is less nephrotoxic.55 Glycopeptides are pregnancy category C, excreted in breast milk, and approved for use in children.11

Clinical Use Dermatologic Indications. Vancomycin is primarily used for the treatment of skin and soft tissue infection (SSTI) caused by MRSA.56 Adverse Effects Cutaneous Reactions and Hypersensitivity. Q9.6 Red man

syndrome and shock secondary to histamine release may follow rapid infusion of vancomycin.57 In addition, vancomycin is one of the most common causes of drug-induced linear IgA bullous dermatosis (LABD).58,59 LABD occurs within 2 to 21 days of vancomycin administration and presents as vesicobullae, erythematous papules, erosions, urticarial plaques, or eczematous patches.60 Multiple studies have demonstrated immunoreactivity to a variety of target antigens in drug-induced LABD, including BP180, LAD285 and the α-3 subunit of laminin-332.60–62 Although toxic epidermal necrolysis (TEN) has been reported rarely, direct immunofluorescence is helpful in differentiation from vancomycin-associated LABD simulating TEN.57,63,64 Other Adverse Effects. Dose-related hearing loss has been reported in patients with renal failure with IV vancomycin. Concurrent administration of vancomycin with aminoglycosides increases the risk of nephrotoxicity.57 Other AE include fever, neutropenia, thrombocytopenia, and phlebitis. Of note, cutaneous and extracutaneous AE are significantly less common with teicoplanin.57 Drug Interactions. Vancomycin may enhance the activity of nondepolarizing muscle relaxants.21 Dosage. See Table 9.2.

Macrolides Erythromycin, Azithromycin, and Clarithromycin The major oral macrolide antibiotics used in dermatology are erythromycin and clarithromycin, with azithromycin being the major azalide agent. Q9.7 Unlike β-lactams, macrolides are bacteriostatic antibiotics, which bind reversibly the (50S) subunit of the

bacterial ribosome, inhibiting ribonucleic acid (RNA)-dependent protein synthesis.65,66 Q9.8 Macrolides also demonstrate specific anti-inflammatory properties, underlying their therapeutic benefit in inflammatory facial dermatoses, such as acne and rosacea.67 Erythromycin was previously useful for SSTI secondary to staphylococcal organisms and in the treatment of acne; however, the emergence of erythromycin-resistant organisms, including S. aureus and Propionibacterium acnes, has limited the current clinical utility of this drug.1,4,68

Pharmacology (see Table 9.1) Antimicrobial Activity. Macrolide antibiotics (from here on “macrolides” also include azithromycin) are effective against Gram-positive organisms, with the notable exceptions of MRSA and enterococcus. Q9.9 As compared with erythromycin, azithromycin and clarithromycin have increased activity against Gram-positive organisms, owing to their PK properties. Unlike erythromycin, clarithromycin and azithromycin possess increased activity against several Gram-negative pathogens.69 Azithromycin is active against E. coli, N. gonorrhoeae, Haemophilus ducreyi, Ureaplasma urealyticum, and Chlamydia trachomatis.65,70 Azithromycin also has activity against organisms isolated in animal bites, such as Pasturella multocida and in human bites, such as Eikenella corrodens.70,71 Both clarithromycin and azithromycin are effective against the atypical mycobacteria Mycobacterium avium-intracellulare, Mycobacterium leprae, and Mycobacterium chelonei.72–74 Clarithromycin is the most active macrolide against M. leprae. Both clarithromycin and azithromycin are active against Toxoplasma gondii, Treponema pallidum, and Borrelia burgdorferi.75–77 Pharmacokinetics. Q9.2 Unless administered in an entericcoated form, erythromycin base is vulnerable to gastric acid inactivation and must be taken on an empty stomach. Azithromycin and clarithromycin are more stable in gastric acid than erythromycin, increasing their absorption. Clarithromycin is well absorbed with or without food, but azithromycin absorption is decreased with food and should be taken 1 to 2 hours before a meal. Azithromycin and clarithromycin demonstrate superior cellular penetration and blood concentrations to a comparable dose of erythromycin.65 Dosages of clarithromycin and erythromycin must be adjusted in renal disease. As azithromycin is subject to hepatic metabolism, no dosage adjustment is required in renal disease.65,66

Clinical Use Dermatologic Indications Indications for Cutaneous Infections. Q9.9 The macrolides

are effective in the treatment of SSTI and demonstrate a highly favorable safety profile. Particularly in oral formulations, macrolides are useful in the treatment of USSTI, including pyodermas, abscesses, infected wounds, infected ulcers, and erysipelas (see Table 9.2). However, erythromycin use is not a treatment of choice for any USSTI, owing to the high prevalence of resistant staphylococcal and streptococcal strains.1,4,6,8,65,68 Other indications for erythromycin include erythrasma, anthrax, erysipeloid, chancroid, and lymphogranuloma venereum.65 Erythromycin is the treatment of choice for early Lyme disease (erythema migrans) in children under 8 years of age. Available data supports the efficacy of azithromycin and clarithromycin for these indications as well. Q9.9 Azithromycin is effective for donovanosis, cat-scratch disease, toxoplasmosis, and Mediterranean spotted fever.65,70 A single

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dose of azithromycin is effective for treatment of uncomplicated urethritis or cervicitis caused by N. gonorrhoea or C. trachomatis. Azithromycin is an excellent choice for infections associated with animal and human bites caused by Pasteurella and Eikenella spp, respectively. Clarithromycin is effective in leprosy, as well as the atypical mycobacterial skin infections caused by Mycobacterium cheloneae, M. simiae, M. avium complex (MAC), M. kansasii, and M. intracellulare.78 Indications for Inflammatory Dermatoses. As an alternative therapy, azithromycin has been used with some success in acne and rosacea.1,4,68,70,79 Because of its prolonged persistence in tissue, intermittent regimens with oral azithromycin have been suggested (250 mg 3 times weekly, after an initial ‘tissue load,’ with daily dosing for 5 days).80–84 In one study, azithromycin was as effective as TCN for rosacea and may be considered in the context of intolerance to TCN.82–84 The use of erythromycin to treat inflammatory dermatoses has declined, given the global prevalence of erythromycin-resistant P. acnes.1,4,66,80–84 Multiple reports have described the efficacy of azithromycin in treatment of confluent and reticulated papillomatosis (CARP). Given its favorable AE profile, azithromycin may be preferred over minocycline in select cases of CARP.65,85,86 The efficacy of macrolides for the treatment of pityriasis rosea is uncertain, given conflicting data and a lack of supportive evidence for this indication from randomized control trials.87–91 Adverse Effects Common Adverse Effects. The most common AE of eryth-

romycin are nausea, abdominal pain, and diarrhea, occurring in 15% to 20% of patients, depending on the oral formulation used (Box 9.3). Erythromycin binds to motilin receptors throughout the GI tract, thereby releasing motilin, which stimulates migrating digestive contractions, leading to GI disturbance.65 Cardiac conduction abnormalities, including QTc prolongation and torsades de pointes, have been associated with erythromycin: risk factors include advanced age, higher dosages, rapid administration, and history of cardiac disease.92 The most common AE associated with clarithromycin is a metallic or bitter taste. Rarely, fixed drug eruption, leukocytoclastic vasculitis and hypersensitivity reactions have been reported.66 Also rare, azithromycin has been associated with irreversible deafness, angioedema, photosensitivity, and hypersensitivity. Macrolides are well described in the pathogenesis of acute generalized exanthematous pustulosis (AGEP). Macrolide antibiotics also rarely cause cholestatic hepatitis and exacerbate myasthenia gravis.65 Use in Infants. Q9.10 Macrolides are excreted into breast milk, and infant exposure during lactation is a risk factor for hypertrophic pyloric stenosis.93,94 Multiple studies have demonstrated a significant association between treatment with macrolide antibiotics and development of pyloric stenosis in infants. This association is stronger when exposure occurs within the first 2 weeks of life.95–97 Therefore, the use of macrolides in infants and lactating mothers should be strictly limited to select cases in which the benefits clearly outweigh the risks. Use in Pregnancy. Data regarding the safety of macrolides in pregnancy are widely variable. In general, oral erythromycin is considered to be safe in pregnancy because only low concentrations cross the placenta. However, the safety of chronic use in pregnancy for acne vulgaris, rosacea, or perioral dermatitis has not been clearly described. Administration of erythromycin estolate for longer than 3 weeks in the second trimester of pregnancy is

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• BOX 9.3 Drug Risks Profile—Macrolides Contraindications Erythromycin—dihydroergotamine, ergotamine, pimozidea Azithromycin—(a) hypersensitivity telithromycin, (b) cholestatic jaundice or hepatic dysfunction with prior azithromycin

Clarithromycin—(a) cholestatic jaundice with prior clarithromycin, (b) hx QTc prolongation, torsades, (c) dihydroergotamine, ergotamine, pimozide

Boxed Warnings None listed

Warnings & Precautionsa Cardiovascular

GI

aAltered

aElevated

cardiac conduction, QTc prolongation, Hx torsades de pointes (uncorrected hypomagnesemia, hypokalemia) Clarithromycin possibly a risk in patients with CAD

Hypersensitivity Reactions Urticaria, angioedema, SJS/TEN, DRESS, vasculitis (HSP)

LFT/hepatitis (esp. clarithromycin), usually reversible upon discontinuation aCaution azithromycin patients significant liver impairment aCDAD (has been reported to occur 2 months after d/c rx)

Neurologic May aggravate weakness in patients with myasthenia gravis

Pregnancy Prescribing Status Traditional US Food and Drug Administration rating—category B (Clarithromycin C)

Newer rating b—compatible

aUnder “Warnings

& Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid. bSee Chapter 65, Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings. CAD, Coronary artery disease; CDAD, clostridium difficile-associated disease; DRESS, drug reaction eosinophils systemic symptoms; GI, gastrointestinal; HSP, Henoch-Schonlein purpura; LFT, liver function tests; SJS/TEN, Stevens–Johnson syndrome/toxic epidermal necrolysis. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https:// www.wolterskluwercdi.com/facts-comparisons-online/).

associated with 10% risk of maternal hepatotoxicity, which is reversible upon discontinuation.24,98 Use of erythromycin during pregnancy is also limited by its rare association with cardiotoxicity.65,92 In a review of maternal erythromycin use over 15 years, erythromycin was persistently associated with cardiovascular defects (risk estimate 1.70; 95% confidence interval [CI], 1.26– 2.39).99 Thus, prolonged use of erythromycin during the first and second trimester of pregnancy should be discouraged.11 In contrast, short-term use of macrolides in the third trimester of pregnancy is subject to a different risk–benefit analysis. In the third trimester, short-term erythromycin safely reduces maternal and infant colonization with group B β-hemolytic streptococcus and reduces the risk of pregnancy loss and low-birthweight infants, in women with genital mycoplasma infections.100 Azithromycin has generally been considered safe for use in pregnancy (Pregnancy Category B). However, data from animal studies of clarithromycin (Pregnancy Category C) have been conflicting. Like erythromycin, clarithromycin should also be used with caution during pregnancy.11 Drug Interactions. Q9.9 Erythromycin, and to a lesser extent clarithromycin, inhibits the hepatic and intestinal (‘first-pass’) CYP system, primarily CYP3A4, leading to decreased metabolic clearance of several drugs, often rapidly after initiation of erythromycin/clarithromycin therapy.101,102 Erythromycin is a more

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potent inhibitor of CYP3A4 than clarithromycin. Both drugs raise plasma levels, prolong the clearance of many drugs, subject to metabolism by CYP3A4, including (Table 9.4): 1. Carbamazepine and phenytoin;102–104 2. Theophylline; 3. Certain benzodiazepines (i.e., triazolam, midazolam); 4. Warfarin, with potential for severe bleeding complications; 5. Cyclosporine, with potential for renal toxicity and hypertension;

6. Drugs with potential for QTc prolongation and torsades de pointes102,105,106 (terfenadine, astemizole, cisapride, and pimozide; all but pimozide have been withdrawn from the market); 7. Some HMG-CoA reductase inhibitors or ‘statins’ (i.e., atorvastatin, simvastatin, lovastatin), enhancing their risk for rhabdomyolysis.101–103 8. Coadministration with ergot alkaloids (dihydroergotamine, ergotamine, etc.) can lead to ergotism and is contraindicated.107,108

TABLE Drug Interactions—Macrolides and Azalides 9.4

Drug Category Relatively High-Risk Drug

Drug Examples

Comments

Interactionsa

Calcineurin inhibitors

Cyclosporine (and oral tacrolimus)

CYP3A4 substrate ↑ drug levels and risk of severe toxicity (HBP, renal failure, hyperlipidemia, others)

Statins

Simvastatin, atorvastatin, lovastatin

same (risk myopathy, rhabdomyolysis)

Benzodiazepines

Alprazolam, triazolam, midazolam

same (risk excessive sedation)

Calcium-channel blockers

All are CYP3A4 substrates

same (hypotension, bradycardia)

Sulfones

Dapsone

same (risk hemolysis, agranulocytosis)

Anticoagulants

Warfarin

R-enantiomer of warfarin (CYP3A4 2nd most important substrate pathway after CYP1A2) risk bleeding

Antigout meds

Colchicine

Possible ↑ myelotoxicity

Antidysrhythmic agents

Amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine

Risk QTc prolongation → torsades de pointes (risk with erythromycin, clarithromycin, azithromycin)

Antibacterials—macrolides

Clarithromycin, erythromycin

same

Antidepressants

Amitriptyline, clomipramine, desipramine, likely others

same

Antipsychotic agents

Haloperidol, olanzapine, phenothiazines, pimozide, ziprasidone

same

β-blockers

Sotalol

same (see Ch. 66 on Drug Interactions for more extensive list of drugs ↑ QTc interval)

SSRI antidepressants

Fluoxetine, fluvoxamine

CYP3A4 substrates, generally modest risk

Hormonal

Estrogens, combined oral contraceptives

In general, modest risk (conceptually venous thromboembolism risk; likely a stronger genetic risk)

Retinoids

Isotretinoin (possibly acitretin)

In general, modest risk (most of very few interactions other mechanisms)

PDE-5 inhibitors

Sildenafil, tadalafil, vardenafil

CYP3A4 substrates (sustained erection, priapism)

H1 antihistamines

Fexofenadine, loratadine

Primary antihistamines (1st or 2nd generation) which are CYP3A4 substrates; historically, terfenadine, astemizole (both off the market) induced torsades de pointes in combination CYP3A4 inhibitors)

Anticonvulsants (aromatic)

Phenytoin, carbamazepine, phenobarbital

CYP3A4 inducers; loss of efficacy azalides, macrolides, interaction takes 1–2 weeks to begin

Rifamycins

Rifampin, rifapentine, rifabutin

same

Antifungals

Griseofulvin

same

Lower-Risk Drug Interactions

aOverall

highest-risk drug interactions indicated in bold italics. CYP, Cytochrome P-450; PDE, phosphodiesterase; SSRI, selective serotonin reuptake inhibitor. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: a Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. (http://www.hanstenandhorn.com/).

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9. Clarithromycin may reduce the absorption of zidovudine (AZT) by 20% and may also reduce the serum levels of didanosine (ddI).109,110 10. In contrast, clarithromycin may significantly increase linezolid serum concentrations when coadministered.111 11. Macrolide-induced digoxin toxicity has been described, because of alterations in gut flora or P-glycoprotein.112–117 Azithromycin minimally inhibits CYP3A4 isoenzymes, and so may be safely coadministered with other drugs.102,118,119 Nonetheless, toxicity has been reported following coadministration of azithromycin with lovastatin, warfarin, cyclosporine, disopyramide, or theophylline.120,121 The potential impact of oral antibiotics on the efficacy of oral contraceptives is reviewed later under the Drug Interactions sections for both TCNs and rifamycins. Dosage. Dosage guidelines for macrolide antibiotics are summarized in Table 9.2. The usual adult dosing schedule for erythromycin base is 250 to 500 mg every 6 to 12 hours, and for erythromycin ethyl succinate, 400 to 800 mg every 6 to 12 hours. The adult dosage of clarithromycin is 250 to 500 mg every 12  hours; a newly available XL formulation (500 mg) permits once-daily dosing. For azithromycin, the adult dosage is 500 mg, given as a single dose on the first day of therapy, followed by 250 mg once daily for 4 additional days (also known as a Z-pak; a 3-day version is also available). For the treatment of uncomplicated chlamydial infections, azithromycin is administered as a single 1-g dose. Localized gonococcal infections may be treated with a single 2-g oral dose. Azithromycin is available in 250, 500, 600 mg tablets, a 2-g extended-release (ER) oral suspension, a 250 mg/5 mL pediatric liquid preparation, and an IV formulation.

Fluoroquinolones Fluoroquinolones (FQ) represent a versatile group of antimicrobials owing to their broad spectrum coverage. Newer agents in this class demonstrate longer half-lives, high oral bioavailability and extensive tissue penetration. Several FQ are useful in dermatology.122 Q9.11 FQ interfere with bacterial deoxyribonucleic acid (DNA) replication via two mechanisms: inhibition of DNA gyrase (bacterial topoisomerase II), an enzyme that regulates supercoiling of bacterial DNA, and topoisomerase IV, an enzyme that allows separation of the topologically linked daughter chromosomes during DNA replication.122 FQ are pregnancy category C and are excreted in breast milk.24 They have been found to impair cartilage formation in immature animals and therefore are usually not recommended for use in patients under 18 years of age.123,124

Pharmacology Antimicrobial Activity. The spectrum of antimicrobial activity of FQ is dependent on the topoisomerase inhibited. FQ that preferentially inhibit DNA gyrase (topoisomerase II) are selective for Gram-negative bacteria, whereas FQ that inhibit topoisomerase IV are more effective against Gram-positive bacteria. Table 9.1 outlines the spectrum of individual FQ. Overall, the FQ are effective against most gram-negative bacteria, particularly Enterobacteriaceae. FQ are also effective oral agents for treatment of USSTI caused by susceptible pathogens.6,8,68 Ciprofloxacin has important use in the treatment of P. aeruginosa, although some strains have become ciprofloxacin-resistant.125 Third and fourth generation FQ, including levofloxacin and moxifloxacin, are effective against S. aureus and S. pyogenes.

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Ciprofloxacin is also highly active against Bacillus anthrax. FQ possess minimal anaerobic activity. Ciprofloxacin, ofloxacin, and levofloxacin are active against Mycobacterium spp, including M. tuberculosis, M. fortuitum, and M. kansasii.126,127 Pharmacokinetics. Q9.2 With the exception of norfloxacin, the oral bioavailability of FQ is excellent and minimally affected by food. However, metal ions coadministered in high concentration, such as in antacids or vitamin/mineral supplements, impair FQ absorption.101,122 Half-lives of individual FQ vary from 3 to 13 hours.128 Except for moxifloxacin, FQ are excreted renally, and thus require dosage adjustment in patients with significantly impaired renal function.129

Clinical Use Dermatologic Indications. Because of high drug levels in the skin and appendages, oral FQ are ideal agents for treating USSTI caused by gram-negative bacteria, such as folliculitis, abscesses, cellulitis, infected ulcers (especially diabetic), Gram-negative toe web-space infections and wound infections.122 FQ are effective for donovanosis and chancroid, as an alternative to first-line agents. The worldwide prevalence of FQ-resistant N. gonorrhoeae ranges from 10% to 100%; therefore FQ are no longer recommended for the treatment of gonorrhea.130,131 Ciprofloxacin is a treatment of choice for cutaneous anthrax.122 Although some efficacy of FQ has been described for acne vulgaris, the use of FQ for this indication is not recommended.80,81,132 Ciprofloxacin is a first-line treatment for severe cases folliculitis caused by Pseudomonas spp (“hot-tub folliculitis”).133 In patients with Gram-negative folliculitis caused by long-term systemic antibiotic therapy, antibiotic selection should be guided by bacterial culture and sensitivity results.134 However, isotretinoin is the treatment of choice for recalcitrant disease. Adverse Effects Common Adverse Effects. GI AE, such as nausea, vomiting,

and diarrhea, is commonly associated with FQ (Box 9.4).122 Common central nervous system (CNS) AE range from mild reactions, such as headaches, dizziness, agitation, and sleep disturbance, to severe reactions, including seizures, psychosis, hallucinations, and depression.122,128,135–137 The mechanism underlying CNS effects may relate to FQ antagonism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).122 FQ use has also been associated with secondary pseudotumor cerebri.138 In addition, FQ demonstrate neuromuscular-blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis; the use of FQ should be avoided in this population.139 Tendinitis and tendon rupture have been observed with FQ, and may be delayed in onset.122,140,141 Risk factors for FQinduced tendinopathy and tendon rupture include female gender, corticosteroid (CS) use, patient age older than 60 years, history of renal failure, diabetes mellitus, history of solid organ transplant, and history of tendinopathy.140–142 In late 2018, the FDA issued a FQ warning for inducing aortic dissection and rupture. Risk factors include hypertension and elderly patients. QTc interval prolongation caused by inhibition of potassium channels has been described with a variety of FQ.143 This risk is increased in patients who are elderly, female, or have additional risk factors for QTc prolongation. Therefore FQ should be avoided in patients with known QTc interval prolongation, torsades de pointes, hypokalemia, hypomagnesemia, or use of specific antiarrhythmic drugs.

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• BOX 9.4 Drug Risks Profile—Fluoroquinolones Contraindications Hypersensitivity to fluoroquinolones, components formulation

Boxed Warnings Tendinitis and tendon rupture Exacerbation of myasthenia gravis

Peripheral neuropathy and CNS effects These SAE may occur together (may occur within hours/weeks)

Warnings & Precautionsa Musculoskeletal

Neurologic

aTendinitis/rupture—esp. concomi-

aPeripheral

tant CS, solid organ transplants, individual at least 60 y/o (can occur without RF)

Cardiovascular aAltered

cardiac conduction, prolonged QTc interval, avoid with hx of torsades, ventricular dysrhythmia, QTc risk drugs (text) Risk of aortic aneurysms and rupture

neuropathy—may occur soon after initiation of rx, avoid in patients with prior peripheral neuropathy aCNS effects—seizures, pseudotumor cerebri, nervousness, tremors, depression, suicidal thoughts (even early in rx)

Hepatic Reports severe hepatotoxicity (ciprofloxacin, levofloxacin)

Pregnancy Prescribing Status Traditional US Food and Drug Administration rating—category C

Newer ratingb—CONTRAINDICATED

aUnder “Warnings

& Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid. bSee Chapter 65, Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings. CNS, Central nervous system; CS, corticosteroids; RF, risk factors; SAE, serious adverse events. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https:// www.wolterskluwercdi.com/facts-comparisons-online/).

Hepatotoxicity may also occur with FQ, but the frequency varies with the agent used. In a case-control study, moxifloxacin and levofloxacin were associated with an increased risk of acute liver injury relative to clarithromycin.144 Hypersensitivity and Photosensitivity Reactions. Hypersensitivity reactions and photosensitivity have also been reported in association with FQ. Phototoxic reactions, including pseudoporphyria and photo-onycholysis, are well-described following treatment with FQ.145–147 Q9.12 In order of decreasing phototoxicity, these agents include lomefloxacin, ciprofloxacin, norfloxacin, and ofloxacin.146 Evening dosing of these agents may minimize phototoxic potential.147 As a class, FQ are generally well tolerated; however, more serious anaphylactoid or anaphylactic reactions, mediated through IgE and non-IgE mechanisms, may rarely occur.148 There is evidence of cross-reactivity among FQ in patients with immediate reactions. However, no clear patterns of hypersensitivity have been identified; therefore formal testing is not recommended.149 Special Populations Use in Pregnancy and Lactation. FQ are generally avoided

during pregnancy and lactation because they are toxic to developing cartilage in experimental animal studies. However, congenital (including cartilaginous) malformations have not been documented following FQ use during human pregnancy.150 Thus use of FQ in pregnancy should be reserved to short-term use only, when a safer alternative therapy is not available. Importantly,

ciprofloxacin is approved by the FDA for postexposure prophylaxis and treatment of anthrax in pregnant women.24 Use in Children—Cartilage Formation Alteration. Q9.10 Studies in immature animals have demonstrated impaired cartilage formation with FQ administration, and therefore these agents are not recommended for routine use in children under 18 years of age.123,124,151,152 However, this recommendation is not evidenced based, given the absence of arthropathy attributable to FQ, despite decades of use in humans. Over a 5-year follow-up period in children who received levofloxacin or a comparator drug, the number of persistent musculoskeletal AE attributable to pharmacologic therapy was equal (one of 1340 in those treated with levofloxacin; one of 893 in those treated with comparator drug).153 The American Academy of Pediatrics recommends that the use of FQ in children should be limited to clinical scenarios in which no safe and effective alternative exists, or in which FQ therapy would serve as an alternative to non-FQ parenteral therapy.123,124,152 Ciprofloxacin and levofloxacin are FDA approved for use in children for postexposure prophylaxis against inhalational anthrax and prevention of plague. Drug Interactions. Q9.2 All FQ show decreased bioavailability when administered with calcium-, aluminum-, or magnesiumcontaining antacids, because of the formation of cation–FQ complexes that are poorly absorbed (Table 9.5).101,122 Decreased GI absorption of FQ has also been noted with coadministration of sucralfate and iron- or zinc-containing products. A practical clinical guideline is to instruct patients to take FQ at least 1 to 2 hours before, and not within 4 hours after, the ingestion of the aforementioned drugs/products.101 Interactions resulting in increased FQ levels and toxicity include: 1. Theophylline metabolism is reduced by ciprofloxacin and norfloxacin, via hepatic CYP isozyme 1A2, resulting in potential toxicity.154 2. The metabolism of caffeine is similarly inhibited, and patients should reduce caffeine intake while taking FQ, to avoid a ‘double espresso-like’ effect. 3. A decrease in warfarin and cyclosporine metabolism has also been documented, although cyclosporine is primarily metabolized by CYP3A4.155,156 CYP1A2 is the pathway by which FQ can interact with warfarin 4. As discussed earlier, certain FQ may increase the risk of torsades de pointes when administered with some antiarrhythmic agents, and are contraindicated with drugs known to prolong QTc interval. Dosage. Ciprofloxacin, levofloxacin, and moxifloxacin are available for parenteral therapy. However, given the excellent oral bioavailabilty of FQ, parenteral therapy has no definitive advantage over the oral therapy for most cutaneous infections. Exceptions include CSSTI or more serious systemic infections, intolerance of oral FQ because of GI toxicity, and required frequent ingestion of agents that impair FQ absorption (see earlier). Some FQ can be given once daily. The preferred dosages for commonly used oral FQ are listed in Table 9.2.

Tetracyclines Tetracycline, Doxycycline, and Minocycline Tetracycline (TCN) agents are the most frequently prescribed antibiotic class in dermatology and are used for both their antimicrobial and anti-inflammatory properties. When discussing the TCN, the designation TCNs refers to these agents as a drug class, with the individual drug tetracycline designated as TCN,

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TABLE Drug Interactions—Fluoroquinolones 9.5

Drug Category Relatively High-Risk Drug

Drug Examples

Comments

Interactionsa

Anticoagulants

Warfarin (R-enantiomer)

R-enantiomer is important substrate of CYP1A2; risk hemorrhage, check INR frequently

Antidysrhythmics

Mexiletine

CYP1A2 substrate, ↑ levels risk QTc prolongation → torsades de pointes (ciprofloxacin > norfloxacin)

Bronchodilators

Theophylline (also aminophylline)

CYP1A2 substrate; ↑ levels risk CNS toxicity (ciprofloxacin > norfloxacin; not other FQ)

Antidysrhythmic agents

Amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine

Risk QTc prolongation → torsades de pointes (FQ greatest risk gatifloxacin, levofloxacin, moxifloxacin)

Antibacterials—macrolides

Clarithromycin, erythromycin

same

Antidepressants

Amitriptyline, clomipramine, desipramine, likely others

same

Antipsychotic agents

Haloperidol, olanzapine, phenothiazines, pimozide, ziprasidone

same

β-blockers

Sotalol

same (note—see Ch. 66 on Drug Interactions for more extensive list of drugs that ↑ QTc interval)

Diabetic drugs

Oral hypoglycemic agents, insulin

Recent FDA alert for ↑↑ and especially ↓↓ glucose, especially in elderly

Inotropic agents

Digoxin

May ↑ serum levels, mechanism unknown

Corticosteroids

Prednisone, others

Long-term use may ↑ risk of tendon rupture with FQ

5-lipoxygenase inhibitors

Zileuton

Minor CYP1A2 substrate; risk hepatotoxicity (ciprofloxacin > norfloxacin; not other FQ)

Antacids

Traditional

Calcium, magnesium (divalent), and aluminum (trivalent) components ↓ absorption of FQ

Other chelating drugs

Iron, zinc

Chelation with these drugs may ↓ absorption of FQ

Miscellaneous drugs

Didanosine, sucralfate

Didanosine buffered; sucralfate an aluminum salt of sulfated sucrose (↓ absorption of FQ)

Foods/beverages

Caffeine (see text “double espresso” effect)

Weak CYP1A2 inhibitor (see substrates above); used preclinical studies to assess CYP1A2 metabolism)

Lower-Risk Drug Interactions

aOverall

highest-risk drug interactions indicated in bold italics. CNS, Central nervous system; CYP, cytochrome P-450; FDA, US Food and Drug Administration; FQ, fluoroquinolone; INR, international normalized ratio. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: a Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. (http://www.hanstenandhorn.com/).

unless otherwise specified. (Only instance in book in which for clarity plural abbreviation will be used) Q9.7 TCNs share 4 fused 6-membered rings, are bacteriostatic, and inhibit bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome.157 Q9.8 In addition to their dose-dependent antibiotic effect, TCNs exhibit a wide variety of direct and indirect antiinflammatory properties that are unrelated to their antibiotic activity.1,2,158–163 Many of these anti-inflammatory properties contribute therapeutically to their established efficacy for treatment of acne, rosacea, perioral dermatitis and other noninfectious inflammatory and bullous skin disorders.2,162–164 These antiinflammatory properties include: 1. Inhibition of the production of neutrophil chemoattractants by P. acnes (i.e., peptide chemotactic factor, lipase); 2. Inhibition of neutrophil migration in vitro and in skin window studies in vivo;

3. Inhibitory activity against granuloma formation in vitro, likely because of protein kinase C inhibition; 4. Inhibition of multiple matrix metalloproteinases (MMP), which are involved in dermal matrix degradation of both collagen and elastic tissue; 5. Downregulation of cytokines involved in the innate immune response; and 6. A possible scavenger effect against reactive oxygen species (ROS).1,2,158–163 Q9.8 Directed modifications of the chemical structure of TCN markedly alter the innate characteristics of the TCN compound to increase or reduce the antibiotic activities and/or anti-inflammatory properties and PK profile.2,161–163 Q9.12 In addition, alterations of the TCN structure may alter its phototoxic potential, which is a dose-related phenomenon more commonly associated with doxycycline than with TCN, and minimally from

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minocycline.80,132,165 Demeclocycline has no dermatologic indications yet is the greatest photosensitizer of the TCN family; this drug has the unique ability to induce nephrogenic diabetes insipidus.165,166 The TCNs are divided into: (1) the short-acting TCN (half-life 6–12 hours); (2) intermediate-acting demeclocycline (half-life 16 hours); and (3) the long-acting drugs doxycycline (half-life 18–22 hours) and minocycline immediate-release (IR, half-life 11–22 hours), and minocycline ER formulations (reduced Cmax and area under curve). As TCNs remain central to the management of acne and rosacea, and as antibiotic resistance has become a global concern, a review of appropriate use of this antibiotic class is imperative.1,4,68,167

Pharmacology Antibacterial Activity General Antibacterial Properties. The TCNs exhibit activity

against many Gram-positive and Gram-negative bacteria, as well as Mycoplasma spp, Chlamydia spp, Rickettsia spp, spirochetes, and some parasites.157 Overall, they possess greater Gram-positive than Gram-negative activity. Many strains of staphylococci, propionibacteria, and group A streptococci are now resistant to TCN, with increasing resistance of P. acnes to TCNs.1,4,68,157,168–171 Mechanisms of Resistance. Q9.5 Two major TCN resistance mechanisms acquired by bacteria are: (1) ribosomal protection, and (2) drug efflux. The latter usually occurs via mobile genetic elements or ‘jumping genes’ (i.e., plasmids, transposons) transferred between strains of the same species.1,68,21 In P. acnes, TCN resistance is mediated exclusively through point mutations in genes encoding the 16S ribosomal RNA.1,172 Pharmacokinetics. Oral TCN, doxycycline, and minocycline are all available as IR formulations for both cutaneous infections and noninfectious dermatologic uses.173–175 Doxycycline modified release (MR), administered as 40 mg once daily, is not to be used for treatment of infection, given the subantimicrobial serum levels.176,177 ER minocycline, administered at 1 mg/kg/day, produces subantimicrobial drug levels and is thus indicated for inflammatory lesions of moderate to severe acne vulgaris.227,229,230 TCNs are lipophilic, reaching high concentrations in skin and nails. Their lipophilic properties allow significant drug levels in the pilosebaceous unit, and can cross the blood–brain barrier.173 The order of lipophilicity among TCNs is minocycline > doxycycline > TCN. Tissue concentrations of doxycycline IR are approximately fivefold greater in soft tissues than in serum, with minocycline IR achieving 47% higher concentrations in skin than in serum.173,174 Q9.2 Although minocycline ER is absorbed even after eating, other TCNs (especially TCN) are better absorbed overall in the fasting state.173,175 However, doxycycline (IR and MR) and minocycline IR are still relatively well absorbed with food intake; a meal reduces GI absorption of doxycycline (IR and MR) by approximately 20% and of minocycline IR by 12%.173–175,177–179 For dermatologic indications, doxycycline and minocycline formulations have multiple major advantages over TCN, including greater GI absorption, greater activity against P. acnes, lower prevalence of P. acnes resistance, less frequent dosing, and less binding within the GI tract by coingested metal ions found in dairy products, vitamin/mineral supplements, and antacids (see text later).1,4,68,80,132,170,173,180,181 Q9.2 Several metallic ions, many contained in high quantities in dairy products (i.e., milk, yogurt), vitamin/mineral supplements, antacids, and antidiarrheal products, can markedly reduce

the GI absorption of TCNs, through chelation of TCNs in the stomach.101,179,182,183 Examples of metallic ions that can reduce TCN absorption include calcium, aluminum, magnesium, iron, zinc, and bismuth. Renal failure prolongs the half-life of most TCNs, except doxycycline, which is excreted primarily by the GI tract in bile and thus is acceptable for use in patients with renal failure. Caution is warranted when prescribing doxycycline for patients with severe liver disease.184 Antibiotic Resistance in Acne. Before reviewing dermatologic uses of TCNs, consider the increasing prevalence of antibiotic resistance and review important resistance reduction strategies, specifically in regards to treatment of acne vulgaris. As stated earlier, the use of antibiotics for acne is associated with the development of resistance in P. acnes, mostly via point mutations.185 In 2003, multiple European countries reported resistance in more than half of P. acnes isolates, predominantly to topical erythromycin and clindamycin, and less so to TCNs.171 1. Because of the development of resistance, the clinical efficacy of topical erythromycin decreased from the 1970s to 2002.185 2. Resistant strains of P. acnes has been found on skin of untreated contacts of acne patients treated with antibiotics. These resistant strains may therefore represent a risk to untreated contacts, especially those with impaired immunity.186 3. Even after discontinuation of therapy, resistance may persist.185 4. Presence of resistant organisms may reduce treatment efficacy.170 Furthermore, evidence has revealed that use of antibiotics for treatment of acne leads to multiple off-target effects. In one crosssectional study (n = 107), patients taking oral TCNs or topical antibiotics for at least 3 months had a threefold increase in the prevalence of S. pyogenes in the oropharynx compared with those who were not on antibiotic therapy (33% vs. 10%).187 In addition, multiple studies demonstrated evidence of increased rates of upper respiratory infections in acne patients treated with oral antibiotic therapy.188,189 Finally, the use of topical antibiotics has been associated with resistance in S. aureus. However, treatment with oral TCNs is associated with a lower S. aureus carriage rate, without increased resistance.190 These findings highlight the need for antibiotic stewardship, as stressed by the Centers for Disease Control and Prevention. Q9.13 The American Academy of Dermatology has issued guidelines for the treatment of acne with systemic antibiotics, to ensure that patients administered antibiotics for acne receive the preferred agent at the correct dosage and for the appropriate duration. Current recommendations are as follows191: 1. Systemic antibiotics are recommended in the management of moderate and severe acne and forms of inflammatory acne that are resistance to topical treatments. 2. Doxycycline and minocycline are more effective than TCN, but neither is superior to each other. 3. Although oral erythromycin and azithromycin can be effective in treating acne, their use should be limited to those who cannot use TCNs (i.e., pregnant women or children 50% of patients with minocycline-induced DHS/ DRESS), pneumonitis, nephritis, myocarditis, cerebritis, and/or thyroiditis may be observed.344,348,350 Possible sequelae, following resolution of DHS after 2 or more months, include hypothyroidism, autoimmune hyperthyroidism, autoimmune type 1 diabetes, and myocarditis.10,291,348,349 Lupus-Like Syndrome. Q9.14 A lupus-like syndrome (LLS) and other autoimmune adverse reactions appear to be unique to minocycline, with multiple case reports, case series and reviews published in association with minocycline IR since the mid 1990s.291,346,357–375 A retrospective cohort study of 94,694 young patients with acne, in which 24.8% were exposed to minocycline IR, 49% to doxycycline, 42.3% to TCN, and 17% not exposed to any TCN, indicated a hazard ratio of 3.11 for minocycline and lupus erythematosus (LE).357 In order of frequency, based on a review of 82 affected patients, minocycline-induced LLS presented with arthralgias (73/82), arthritis (45/82), fever (38/82), and skin eruption (29/82).351 In another review of 57 cases, polyarthralgias or polyarthritis was present in all, with cutaneous manifestations including ‘rash’, livedo reticularis, oral ulcerations, subcutaneous nodules, and alopecia.361

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Importantly, the emergence of a positive antinuclear antibody (ANA) test, during drug therapy, does not equate with autoimmune disease. In addition, most patients with newly formed autoantibodies do not develop clinical disease.376 It is also important to realize that drug-associated autoimmune reactions, including systemic LLS, do not often meet the established American Rheumatology Association (ARA) criteria required for diagnosis of idiopathic disease.363 In addition to rheumatologic involvement, minocycline-induced LLS has been associated with autoimmune hepatitis, hyperthyroidism, progressive respiratory distress, and cutaneous vasculitis.291,358,361,363,368,372–374 Antidouble-stranded DNA (anti-dsDNA) antibodies may be positive, typically considered to be a relatively specific marker for idiopathic systemic LE.351,358–360,372,373,375 Conversely, minocycline-induced LLS has a low rate of positivity for antihistone antibodies.351,372,373 As with drug-induced DHS/DRESS and SSLR, discontinuation of the causative agent, as soon as possible, is vital, although the rate of resolution for minocycline-LLS varies greatly. Vasculitis. Minocycline-induced cutaneous polyarteritis nodosa (PAN) and vasculitis, presenting as reticulated (livedoid) erythema and/or subcutaneous nodules usually on the extremities (which is reversible), presents after 2 or 3 or more years of minocycline use.377– 379 Serologic testing has shown perinuclear (p)ANCA positivity, suggesting the term ‘drug-induced ANCA-positive vasculitis’.378,379 Hepatotoxicity (Autoimmune). Q9.14 As hepatotoxicity is a common feature of both DHS/DRESS (DRESS current preferred name) and autoimmune hepatitis associated with minocycline therapy, differentiation of potential clinical presentations is important for the clinician. A report published in 2000 indicated that hepatic reactions accounted for 6% of all minocycline AE (493/8025) reported to the World Health Organization (WHO). Minocycline-induced hepatotoxicity can occur early, with a median exposure time of 35 days in DHS/DRESS and 365 days in autoimmune hepatitis or as part of LLS.373,380–382 Other Potentially Serious Adverse Effects. Immune thrombocytopenia presenting as Schamberg disease, and neutropenia as a component of LLS, have been reported with minocycline use.369,370 Demeclocycline has been associated with diabetes insipidus and is used to treat syndrome of inappropriate antidiuretic hormone (see earlier).166 TCNs may augment neuromuscular blockade.157 Use in Pregnancy and Lactation. Q9.15 TCNs are pregnancy category D, and are reported to be contraindicated in the second and third trimesters of pregnancy.24,383 Potential concerns include AE on fetal teeth and bones, congenital defects, maternal hepatotoxicity, and miscellaneous effects. However, these events are extremely rare with doxycycline and observation studies support the relative safety of doxycycline compared with older TCNs, in both pregnancy and children. In a systematic review, there was no correlation between the use of doxycycline during pregnancy and teratogenic effects or dental staining in children.254 Thus, in the setting of certain infections, (e.g., early treatment of RMSF) the benefits of using doxycycline generally outweigh the risks.384 However, the use of TCNs at any time during pregnancy for inflammatory disorders (i.e., acne vulgaris, rosacea) is not recommended.132 Q9.10 TCNs are excreted in breast milk in high concentrations, but very low concentrations are observed in breastfed infants, a reflection of chelation by calcium in breast milk.24,383 Nonetheless, TCNs should be avoided during lactation, unless the benefits clearly outweigh the risks.385 Prior guidelines suggested that TCN should be avoided (apart from life-threatening infections) in children younger than 9 years of age, owing to yellow staining of teeth, and possibly other AE on the development of

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bones.24,384,386 However, more recent evidence has shown that doxycycline binds less readily to calcium than other TCNs with a minimal risk of dental staining, following a short course of administration.387 The American Academy of Pediatrics permits use of doxycycline for less than 21 days in children of all ages.388 Drug Interactions. TCNs may potentiate the pharmacologic effects and toxicity of warfarin, lithium, theophylline, digoxin, methotrexate, and insulin39,40,101,389 (Table 9.6). Pseudotumor Cerebri. The augmented risk of BIH caused by concurrent use of TCNs and oral retinoids (i.e., isotretinoin, acitretin) is controversial and based on the product monograph from the original manufacturer of oral isotretinoin.390 As TCNs and oral retinoids have both been independently associated with BIH, concern regarding an additive or synergistic effect has been noted, but not scientifically evaluated. Published clinical data are needed to more definitively assess the true risk of this interaction. Some cases of BIH associated with oral isotretinoin occurred in patients also using TCNs for acne treatment, based on data maintained by the manufacturer.391 It is prudent to avoid coadministration of TCNs and oral retinoids, whenever possible.390 Dosing. Tables 9.2 and 9.7 contain general dosage guidelines for commonly used TCNs.

Rifampin and Other Rifamycins The rifamycins include rifampin, rifapentine and rifabutin. Rifampicin is synonymous with rifampin. Of these, rifampin in the most commonly used agent in dermatology. These agents are well absorbed and used for systemic therapy primarily for mycobacterial disease (including tuberculosis) and select invasive staphylococcal infections (as part of combination therapy).

Pharmacology Mechanism of Action. Q9.11 Rifampin acts by binding to the β-subunit of bacterial DNA-dependent RNA polymerase, directly blocking the elongating messenger RNA (mRNA) synthesis.392,393 This effect is concentration-dependent.394 Activity against M. tuberculosis relates to mycolic acid complexation within the cell membrane, allowing easy penetration of the drug into the cell. Mechanism of Resistance. Resistance to rifampin arises because of missense mutations in the rpoB gene (encodes the β-subunit of bacterial DNA-dependent RNA polymerase) and occurs in a variety of bacteria including M. tuberculosis, S. pneumoniae, S. aureus (including MRSA) and Rickettsiae.395 In addition, the rate of spontaneous resistance in multiple bacteria, including M. tuberculosis, to rifampin is high and predictable. For this reason, rifampin should rarely be used as monotherapy, except when used for prophylaxis against Neisseria meningitidis or H. influenzae.396 Antimicrobial Activity. Rifampin is useful for treatment of intracellular pathogens, owing to its ability to achieve high intracellular concentrations. Rifampin exhibits a broad spectrum of antibiotic activity that includes Mycobacterium spp, including M. tuberculosis and M. leprae, staphylococci (both coagulase-negative and coagulase-positive), N. meningitidis, N. gonorrhoeae, H. influenzae, and several Chlamydia spp.393,397,398 However, gram-negative coverage is poor overall. Rifampin is FDA approved for the treatment of tuberculosis (TB) and is best used in combination therapy and for the meningococcal carrier state (but not for active disease, owing to the rapid development of resistance).392 When used for atypical mycobacterial infections or leprosy, rifampin is administered in combination with other anti-TB drugs and can be used over several

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TABLE Drug Interactions—Tetracyclines (Focus on Doxycycline & Minocycline) 9.6

Drug Category Relatively High-Risk Drug

Drug Examples

Comments

Interactionsa

Retinoids

Isotretinoin > acitretin

Concomitant use may ↑ risk of pseudotumor cerebri = idiopathic intracranial hypertension

Inotropic agents

Digoxin

May ↑ levels of digoxin in about 10% of patients (which may persist)

Xanthine bronchodilators

Theophylline

May ↑ levels of theophylline and toxicity, including CNS adverse effects

Anticoagulants

Warfarin

May ↑ levels/anticoagulant effect (altered gut flora ↓ vitamin K dependent clotting factors); can check INR 1 week after initiate tetracycline therapy (warfarin/CYP interactions much more important)

Psychotropic agents

Lithium

Uncertain mechanism

Photosensitizers

Porphyrins, psoralens, retinoids

Order of photosensitization potential doxycycline, demeclocycline > tetracycline >> minocycline

Hormonal contraceptives

Various

Controversial; consensus is no ↑ risk contraceptive failure (in theory altered enterohepatic recirculation)

Lower-Risk Drug Interactions Antacids

Traditional

Calcium, magnesium (divalent), and aluminum (trivalent) components ↓ absorption of tetracyclines

Foods

Milk

Calcium content ↓ absorption of tetracyclines

ACE inhibitors

Quinapril

This ACE inhibitor has relatively high magnesium content

Other chelating drugs

Bismuth salts, iron, zinc

Chelation with these drugs may ↓ absorption of tetracyclines

Bile acid sequestrants

Cholestyramine, colestipol

May ↓ absorption of tetracyclines

aOverall

highest-risk drug interactions indicated in bold italics. ACE, Angiotensin-converting enzyme; CNS, central nervous system; CYP, cytochrome P-450; INR, international normalized ratio. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: a Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. (http://www.hanstenandhorn.com/).

TABLE Commonly Used Oral Tetracyclines—Dosage Guidelines 9.7

Generic Name

Tablet/Capsule Sizes (mg)

Adult Dosage

Tetracycline a,c

250, 500

250–1500 mg/day (QD or BID)

Doxycycline a c

20g, 50, 75b, 100, 150b

50–200 mg/day (QD or BID for total daily dose)

Doxycycline MRe,g,f

40 mge

40 mg once dailyg,f

Minocycline IRc,h

50, 75, 100

50–200 mg/dayh (QD or BID for total daily dose)

Minocycline ERd,g,j,k,l

45, 55, 65, 80, 90, 105, 115, 135

1 mg/kg/dayg,j,k,l (given once daily, all are ERd)

BID, Twice a day; QD, every day. aLiquid or suspension formulations available. bEnteric-coated formulation available and shown to reduce incidence of gastrointestinal (GI) adverse effects (not extended release). cImmediate-release formulation = IR. dExtended-release formulation (tablet) = ER. eModified-release formulation (capsule) = MR. fAnti-inflammatory dose doxycline (30 mg IR + 10 mg MR capsule once daily) produces anti-inflammatory effects without antibiotic effect with US Food and Drug Administration (FDA)–approval for treatment of inflammatory lesions of rosacea. gNot to be used for treatment of infections hIncidence of vestibular adverse effects affected by release rate of individual IR formulation and dose administered. j1 mg/kg once daily dose with FDA-approval for treatment of inflammatory lesions in moderate to severe acne vulgaris (nonnodular type) in patients ≥12 years of age. kGI absorption not affected by administration with or without food. l1 mg/kg once daily dose with same efficacy, but lower incidence of acute vestibular adverse effects in pivotal trials as compared with 2 mg/kg/day and 3 mg/kg/day.

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months.392,393 A high level of activity against atypical mycobacteria, especially M. kansasii and M. marinum, has been noted. Q9.16 Although S. aureus strains may be sensitive to rifampin in  vitro, resistance often develops rapidly when monotherapy is used.8,397–399 Rifabutin and rifapentine have a similar overall spectrum of activity as rifampin.400,401 Q9.5 Rifampin-resistant strains may appear equally susceptible to rifabutin in  vitro, but a clinical response is not likely, as resistance is controlled by rpoB mutation in both drugs.393 Pharmacokinetics. Rifampin is available for oral or IV use, and is readily absorbed from the GI tract; however, peak serum concentrations may show wide variation between individuals.392 Q9.2 Absorption is improved when oral doses are taken on an empty stomach and may be delayed or reduced if taken with food and in patients with diabetes and/or HIV infection.392,402,403 Owing to extensive hepatic metabolism, dosage adjustment of rifampin is not necessary in patients with mild renal failure at doses of 600 mg or less daily.392,404 However, caution should be used when rifampin is administered to patients with significant hepatic disease, especially when in combination with other hepatotoxins (such as isoniazid). Rifampin is a potent inducer of multiple CYP isoforms, which results in increased hepatic metabolism and more rapid clearance of wide variety of drugs.39,40,101,405 Rifabutin is a less potent inducer of CYP enzymes with relevance to HIV/AIDS patients, discussed in the Drug Interactions section.393,400,401 Rifapentine is an oral, long-acting analog of rifampin that may be given once weekly for TB treatment.

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Methicillin-Sensitive Staphylococcus Aureus Infections. Q9.16 Rifampin is effective against USSTI caused by S. aureus. However, rapid emergence of resistance limits its efficacy, especially as monotherapy.8,399,397,404,415,416 Other Infections and Related Diseases. Cutaneous leishmaniasis and rhinoscleroma, caused by intracellular pathogens, also respond to rifampin therapy.417 Limited evidence supports the efficacy of rifampin for the treatment of human granulocytic anaplasmosis as an alternative to doxycycline (in pregnancy patient or children 99%

99.8%

11%–12%b

84%

Metabolism

Significant first-pass hepatic metabolism; CYP2C9, 1A2, 3A4, 2C8, 2C19 major isozymes; no active metabolites

Extensive metabolism in liver by CYP3A4; active metabolite: hydroxyl-itraconazole

Little first-pass hepatic metabolism, much of dose is excreted as unchanged parent drug

Hepatic, major metabolites are 6-demethylgriseofulvin and its glucuronide conjugate

Excretion

Renal 70%; clearance decreased 50% in renal impairment or hepatic cirrhosis

Renal 40% inactive metabolites; fecal 3%–18% parent drug

Renal 80% as parent drug, 11% metabolites; 2% feces

Renal 50%, 1% excreted unchanged in urine; 36% in feces

IV, Intravenous. aNonlinear PK: terminal t 1/2 is dose-dependent and not predictive of accumulation or elimination. bFluconazole is much less lipophilic, thus more hydrophilic than other azoles including itraconazole; this accounts for low protein binding.

CH3

N N

F

C(CH3)3

N

N N

N

N OH

F Terbinafine

Fluconazole

N N N

CH3

O

O

H3C N N

N

N

O

O

N H Itraconazole

• Fig. 10.1

Drug structures—terbinafine, itraconazole, fluconazole.

CI

Cl

101

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of the broader category of azole antifungals. Q10.2 Terbinafine and itraconazole have bioavailabilities of approximately 40% and 55%, respectively, and both drugs are extensively metabolized by the liver (see Table 10.2).1,5 In contrast, fluconazole has a bioavailability of greater than 90%, and undergoes little hepatic metabolism. Absorption of itraconazole in a fasting state, or in individuals with relative or absolute achlorhydria (e.g., those on H2 inhibitors, antacids, or proton-pump inhibitors), may be increased when the itraconazole is administered with at least 8 oz of a cola beverage.1 When fluconazole 50 to 400 mg is given once daily, steady-state concentrations are achieved within 5 to 10 days, but may be attained more rapidly by doubling the dose on the first day.4 In patients with liver cirrhosis, terbinafine clearance was reduced by approximately 50% compared with normal volunteers, and itraconazole elimination half-life showed a two-fold increase.1,5 Careful monitoring is suggested in these patients. In patients with renal insufficiency (serum creatinine >3.4 mg/dL, or creatinine clearance 20 mg/kg/day do not significantly increase the complete cure rate compared with less than 20 mg/kg/day.67 Griseofulvin appears to provide superior efficacy to terbinafine, when treating tinea capitis, because of Microsporum sp.66,67 In some countries, including the United States, griseofulvin oral suspension, 125 mg/5 mL, is available (see Table 10.1). Alternatively, the tablets can be pulverized and administered with food. Terbinafine. Before 2007 terbinafine tablets were commonly prescribed off label for tinea capitis infections using a weightbased dosing regimen (see Table 10.5).64,65 In 2007 the FDA approved a terbinafine oral granule formulation for tinea capitis. The label-indicated weight-based dose for the granule formulation is: less than 25 kg, 125 mg daily; 25 to 35 kg, 187.5 mg daily; over 35 kg, 250 mg daily (which is the adult dose), which is given for 6 weeks.6 Although the label-indicated duration of therapy is 6 weeks, pulsed dosing regimens and shorter durations have also been reported to be effective.65,69,70 A dose-response study using terbinafine found that doses >4.5 mg/kg daily were more likely than lower doses to produce a cure in both Trichophyton and Microsporum infections, with duration of therapy being less

important.71,72 A recent meta-analysis has demonstrated that terbinafine has superior efficacy to griseofulvin for treating tinea capitis because of Trichophyton spp.66 Itraconazole. Itraconazole continuous and pulse therapies have been used to treat tinea capitis effectively. The dosing regimens used are 5 mg/kg daily for 4 to 8 weeks, or, in the case of pulse therapy, 5 mg/kg daily for 1 week a month, given for 2 to 4 months (see Table 10.5).65,68 Where the oral solution is used, dosage is reduced to 3 mg/kg daily, whether used continuously or as pulse therapy.65,73 Fluconazole. A limited number of studies have shown that continuous fluconazole 6 mg/kg daily lasting 3 weeks can effectively treat tinea capitis (see Table 10.5).64,65 A comparative study of 5 mg/kg daily for 4 weeks showed similar efficacy to griseofulvin 15 mg/kg daily for 6 weeks.74 Once weekly therapy with fluconazole for tinea capitis has also been found to be effective.75,76 Tinea Corporis, Tinea Cruris, and Tinea Pedis. Q10.10 Typically, successful treatment is provided by topical antifungal medications; oral antifungals are not generally approved for these indications. Off-label use of oral antifungals may be practical where the tinea involvement is extensive and application of a topical either is not feasible or successful.42 Griseofulvin. Griseofulvin is indicated in the United States for the treatment of tinea infections that would not be expected to respond satisfactorily to topical antifungals. Suggested dosage for tinea corporis/cruris is 250 mg twice daily, until a cure is reached.77 For tinea pedis, the suggested dosage is 660 or 750 mg daily for 4 to 8 weeks.78 Terbinafine. Terbinafine has been used for tinea corporis/cruris at 250 mg daily for 2 to 4 weeks, and for tinea pedis at 250 mg daily for 2 to 6 weeks.77,78 Itraconazole. A continuous itraconazole regimen of 200 mg daily for 1 week is recommended for tinea corporis/cruris, although a regimen of 100 mg daily for 2 weeks has also been reported to be effective.77,79,80 For tinea pedis, itraconazole regimens of 100 mg daily for 30 days or 4 weeks, 400 mg daily for 1 week, and 200 mg daily for 2 to 4 weeks have been reported.42,78,81 Fluconazole. The suggested dose of fluconazole for tinea corporis/cruris is 150 to 300 mg once weekly, administered for 2 to 4 weeks.77 The most frequently reported dosage for tinea pedis is 150 mg once weekly, administered for 2 to 6 weeks.82–85 Pityriasis (Tinea) Versicolor and Seborrheic Dermatitis. As with dermatophyte infection, the Malassezia yeasts associated with tinea versicolor and seborrheic dermatitis are most often successfully treated with topical therapy. However, oral medications are occasionally used off label, particularly when large areas of the body are affected.42 It should be noted that even though symptoms of tinea versicolor infection may resolve within 2 weeks of therapy, pigmentation abnormalities may persist for many months before returning to normal.86 Recurrence of tinea versicolor infection is common, particularly in warmer months of the year.87 Topical corticosteroids (TCS) are commonly used for seborrheic dermatitis, but alternative therapies are commonly used to avoid adverse events associated with prolonged TCS use.88 Q10.7 Griseofulvin and terbinafine have not been effective in tinea versicolor infection.86,87 Based on a meta-analysis, itraconazole therapy (200 mg daily given for 5–7 days or 100 mg daily for 2 weeks) was effective in pityriasis (tinea) versicolor.89 Fluconazole doses of 300 mg weekly for 1 to 4 weeks have shown high rates of mycologic cure.42,89 For seborrheic dermatitis, dosages of oral antifungals used include itraconazole 200 mg daily for 7 days, and terbinafine 250

TABLE Dosing for Tinea Capitis in Children 10.5

REGIMEN

Formulation

ITRACONAZOLE CONTINUOUS

TERBINAFINE CONTINUOUS

Oral Granules

Tablets

Dose/kg option

ITRACONAZOLE a PULSE

FLUCONAZOLE CONTINUOUS

FLUCONAZOLE PULSE

GRISEOFULVIN CONTINUOUS

Capsules

Oral Solution

Capsules

Tablets

Oral Solution

Tablets

Tablets

Oral Solution

5 mg/kg/day

3 mg/kg/day

5 mg/kg/day

6 mg/kg/ day

3–6 mg/kg/day

8 mg/kg once weekly

Microsize: 20–25 mg/ kg/day

Microsize (125 mg/5 mL): 20–25 mg/ kg/day

Ultramicrosize: 10–15 mg/kg/day 6 weeks

35 kg

250 mg/day

2–6 weeks (T. tonsurans) 8–12 weeks (M. canis)

62.5 mg/day

21–40 kg

125 mg/day

>40 kg

250 mg/day

aItraconazole

pulses are 1 week of active treatment followed by 3 weeks off drug.

6 weeks

2–4 pulsesa

3 and 6 weeks

3 weeks

4–8 weeks

≥6 weeks

≥6 weeks

Systemic Antifungal Agents

10–20 kg

2–4 weeks (Trichophyton spp.) 4–6 weeks (Microsporum spp.)

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Duration

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mg daily for 4 weeks.42,88,90,91 Patients with facial lesions did not benefit from terbinafine treatment.91 Prophylaxis of Tinea Versicolor. A single 400 mg dose of itraconazole once monthly for 6 months may be useful as prophylaxis for tinea versicolor patients who suffer recurrent outbreaks.86

Oral Antifungal Use in Children With Superficial Fungal Infection With the exception of tinea capitis, most superficial dermatophyte infections are infrequently diagnosed in children, and few published data exist on pediatric use of oral antifungals in these other conditions. As a result, oral antifungals are typically not formally approved for use in children; however, pediatric use has been documented widely in the medical literature and has typically demonstrated a safety profile similar to use in adults.92–94 When using oral antifungals in children, dosing regimens are typically adjusted by weight, as in tinea capitis dosing. Where swallowing the tablets or capsules may be an issue, terbinafine tablets can be crushed or cut up and terbinafine ‘granules’ can be sprinkled on food; itraconazole capsules can be opened and mixed with fatty foods, such as peanut butter.95 Oral suspensions have been developed for many of the oral antifungal medications, which can provide easier dosing for children. These suspensions may have improved pharmacologic qualities and different safety profiles compared with capsule or tablet formulations; therefore, suggested dosing regimens may differ and some formulations may not be used interchangeably. Children With Onychomycosis. As few children present with distal lateral subungual or proximal subungual onychomycosis (DLSO and PSO, respectively), no oral antifungal has been approved for use in children with dermatophyte onychomycosis. For superficial white onychomycosis or milder cases of DLSO, topical therapy may be preferred over the use of oral antifungals. The choice of therapy should take into account the causative organism, concomitant drug therapies, cost-effectiveness, patient preference, and physician familiarity with the antifungal agents.95 Mycologic confirmation of infection is suggested before initiation of any oral agent.95,96 Terbinafine. Both terbinafine and itraconazole have been reported as effective and safe when used off label for onychomycosis in children.41,97–101 With terbinafine, the duration of therapy is similar to that in adults: fingernail and toenail onychomycosis for 6 and 12 weeks, respectively.95 The suggested terbinafine dosage schedule is for patients over 40 kg, 250 mg (= adult dose) daily; 20 to 40 kg, 125 mg daily; and less than 20 kg, 62.5 mg daily.95 Itraconazole. For itraconazole capsules, the suggested dosage is 2 and 3 pulses for fingernails and toenails, respectively.95 Each pulse is 5 mg/kg daily lasting for 1 week, or for those over 50 kg, 200 mg twice daily (= adult dose); 40 to 50 kg, 200 mg daily; 30 to 40 kg, 100 mg daily alternating with 200 mg daily; 20 to 30 kg, 100 mg daily; and 10 to 20 kg, 50 mg on alternating days or 3 times a week. Itraconazole oral solution given as pulse therapy may be another option, at dosages of 3 to 5 mg/ kg daily.95,102 Fluconazole. Reported use of fluconazole for children with onychomycosis is limited. Use of fluconazole for dermatophyte onychomycosis in general requires relatively long-term therapy. Suggested dosage is an intermittent regimen of 3 to 6 mg/kg once weekly for 18 to 26 and 12 weeks, respectively, for toenail and fingernail onychomycosis.95,96

Deep Fungal Infections Terbinafine. Successful use of terbinafine has been reported

in subcutaneous and systemic mycoses, such as chromoblastomycosis, sporotrichosis, fungal mycetoma, aspergillosis, and histoplasmosis.103 Terbinafine regimens are not clearly established; however, effective dosing for systemic mycoses would appear to require 500 to 1000 mg daily.103 Itraconazole. Itraconazole capsules are indicated for the treatment of the following fungal infections: blastomycosis (pulmonary and extrapulmonary), histoplasmosis (including chronic cavitary, pulmonary, and disseminated, nonmeningeal disease), and aspergillosis (pulmonary and extrapulmonary in patients who are intolerant of or refractory to amphotericin B therapy).1 Life-threatening histoplasmosis and blastomycosis may require intravenous itraconazole.104 Fluconazole. Fluconazole is effective for systemic Candida infections, including candidemia and disseminated candidiasis, and is available as an intravenous formulation.4,104 High-dose oral fluconazole (400–600 mg daily) has been recommended for coccidioidal meningitis; however, fluconazole has relatively poor efficacy against endemic mycoses, such as histoplasmosis, blastomycosis, and paracoccidioidomycosis.104,105 The high oral bioavailability of fluconazole is an asset, but the narrow spectrum of action limits its use as a prophylactic.104 Other Off-Label Uses for Oral Antifungals Terbinafine. There have been isolated reports of terbinafine use

in patients with Majocchi’s granuloma,106 tinea imbricata,107,108 cutaneous sporotrichosis,109 black piedra,110 aspergillosis,111 and chromoblastomycosis.112 Itraconazole. Itraconazole may also be effective in the treatment of Majocchi’s granuloma,34 HIV-associated eosinophilic folliculitis,113 tinea imbricata,107 vaginal candidiasis, chronic mucocutaneous candidiasis,62,114 cutaneous sporotrichosis,109 and other C. albicans infections.61 Fluconazole. Fluconazole is effective in the treatment of cutaneous candidiasis, using 150 mg once weekly given for 2 to 4 weeks.82,115 Griseofulvin. Griseofluvin, 500 mg twice daily for 4 to 6 weeks, has been effective treatment for tinea imbricata, but may require concomitant topical therapy.108

Contraindications All of the oral antifungals are contraindicated for patients who are allergic to the drug or its excipients. See Risks Profiles for terbinafine, itraconazole, and fluconazole for a succinct summary (Boxes 10.1 to 10.3). Terbinafine. Terbinafine (capsule or granule formulation) is not recommended for patients with chronic or active liver disease.5,6 Terbinafine clearance is reduced by approximately 50% in patients with renal impairment (creatinine clearance > sertraline)

same (common combinations with doxepin, amitriptyline; potentially with terbinafine as well)

NSRI antidepressants

Bupropion

same

HIV-1 protease inhibitor

Ritonavir

same

Antipsychotics

Haloperidol, thioridazine

same

Anticonvulsants

none

No known CYP2D6 inducers (members of these 3 groups inducers of other major CYP isoforms)

Rifamycins

none

same

Antifungals

none

same

NSAID

Celecoxib

Weaker CYP2D6 inhibitors

Antimalarials (4-aminoquinoline structure)

Hydroxychloroquine

same

H2 antihistamines

Cimetidine

same

Relatively High-Risk Drug

Interactionsa

Lower-Risk Drug Interactions

aOverall highest-risk drug interactions indicated in bold italics. CYP, Cytochrome P-450; HIV, human immunodeficiency virus; NSAID, nonsteroidal anti-inflammatory drugs; NSRI, nonselective reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. The dramatic increase in number of drug interactions in medicine requires some degree of selectivity in these tables (common usage, relative risk, focus on outpatient rx)

Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. (http://www.hanstenandhorn.com/).

Adverse Effects Terbinafine. Terbinafine is considered a safe medication for the gen-

eral population, as well as children, the elderly, transplant patients, diabetics, and HIV patients.116 The safety profile of the oral granule formulation is comparable to that of the tablet formulation (see Table 10.6).5,6 The more common adverse effects (AE) with terbinafine use are headache, gastrointestinal symptoms (diarrhea, dyspepsia, abdominal pain, nausea, and flatulence), dermatologic manifestations (rash, pruritus, urticaria), liver enzyme abnormalities greater than or equal to twice the upper limit of normal, taste disturbance, and visual disturbance.5 Events were noted in small proportions of subjects and were generally mild, and transient.

Rare severe reactions have been noted with terbinafine. Q10.12 Severe skin reactions, such as erythema multiforme, toxic epidermal necrolysis, and Stevens–Johnson syndrome, were reported with oral terbinafine use in 38, four, and nine cases, respectively, out of 2313 adverse reactions reported in the World Health Organization worldwide database (data reported December 1996).117 Severe skin reactions may present initially as a serum sickness-like reaction.117,118 Rare development of idiosyncratic hepatobiliary dysfunction has been reported (1:45,000–1:120,000).119,120 Hepatitis produced by terbinafine typically develops within 4 to 6 weeks of treatment initiation, and has the features of both hepatocellular necrosis and cholestatic injury.120 In most cases, liver functions return to normal several months after stopping the medication.120

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Terbinafine has been reported infrequently to precipitate or exacerbate cutaneous and subacute cutaneous lupus erythematosus, and should be discontinued in patients showing signs of lupus erythematosus.5 Q10.11 Postmarketing data also revealed several cases of subjects experiencing depressive symptoms during use of terbinafine.5 Terbinafine is rated as pregnancy category B and is not recommended for routine use in pregnant or nursing women. No effects on testosterone levels were detected with terbinafine use in a healthy male population.121 Itraconazole. With itraconazole, the common AE are headache, gastrointestinal disorders, and cutaneous disorders (Table 10.7).1–3 When itraconazole is given as a pulse regimen for the treatment of onychomycosis, it may be associated with an improved AE profile compared with the continuous regimen using this triazole.122 Q10.12 In the General Practice Research Database in the United Kingdom sampling nearly 27,000 patients, two cases of serious skin disorders were found with itraconazole use: angioedema (one case) and erythema multiforme (one case).123 Stevens– Johnson syndrome has been rarely reported with itraconazole.1 Abnormal liver function tests were found in 3% of 1845 patients treated with continuous itraconazole compared with 1.9% of 2867 patients treated with pulse itraconazole (200 mg twice daily, for 1 week out of each month).122 Serious adverse liver events were recorded in 3.2 per 100,000 prescriptions.120 The estimated incidence of itraconazole inducing clinically significant symptoms and signs of hepatobiliary dysfunction, for which no other cause was apparent, is 1:500,000.119 Itraconazole is rated as pregnancy category C and is not to be used in women who are pregnant, planning a pregnancy, or nursing. In contrast to ketoconazole, use of itraconazole showed no effect on androgen levels and that alteration of male reproduction is unlikely.124,125 Safety profiles are similar for capsules as the oral suspension.1,2 Preclinical testing of the hydroxy-propyl-β-cyclodextrin vehicle used in the itraconazole oral suspension found some potential for pancreatic adenocarcinomas in rats, but no other tested animal species.2 The potential for carcinoma development in humans has not been determined. Fluconazole. Both at the doses used in dermatology and at higher doses, fluconazole has shown a favorable AE profile.4,126– 128AE profiles seen in pediatric fluconazole use are similar to those in adults.4 The most frequently reported AE in clinical trial patients receiving these azoles are headache, nausea, vomiting, abdominal pain, and diarrhea (see Table 10.7).4,10–12,120,123,126–128 Q10.12 Cases of toxic epidermal necrolysis, Stevens–Johnson syndrome, angioedema, and erythema multiforme have been reported with fluconazole.4,10,120,123,128 Rare cases of serious hepatic toxicity have been reported, with no obvious relationship to daily dose, therapy duration or other factors.4 Self-limiting hepatic and biliary abnormalities were noted in 0.5% of patients using fluconazole, whereas elevated enzyme levels, particularly aspartate aminotransferase (AST), occurred in 10% of subjects using chronic fluconazole therapy.120 Fluconazole is rated as pregnancy category D, with birth defects being noted by a few case reports in subjects using a high doses (400–800 mg/day). Fluconazole, should not be used in women who are pregnant, planning a pregnancy, or nursing. In contrast to ketoconazole, fluconazole at 25 to 50 mg/day showed no significant effect on testosterone levels in healthy male volunteers.129 Voriconazole. It is of historical interest that voriconazoleinduced photosensitivity reports have followed by squamous cell

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carcinoma and melanoma.10 Furthermore, a variety of visual disturbance have been reported in clinical trials and postmarketing surveillance.10

Drug Interactions In general, before prescribing a new drug, it is important to obtain a complete history of all drugs the patient is currently taking, both prescription and nonprescription. The inquiry should extend to herbal and recreational agents. Q10.13 The potential drug interactions associated with terbinafine are listed in Table 10.6.5,6 Terbinafine has relatively few drug interactions compared with the azoles. Terbinafine has been reported to inhibit CYP2D6.5,6 Clinicians should be cautious regarding concomitant administration of terbinafine with CYP2D6 substrates, such as the tricyclic antidepressants doxepin and amitriptyline. The azole drugs share many important drug interactions (see Table 10.7). Coadministration of itraconazole (capsules, injection, or oral solution) with cisapride, pimozide, quinidine, dofetilide, or levacetylmethadol (levomethadyl) is contraindicated.1 Q10.14 Similarly, concomitant use of fluconazole with cisapride, or the antihistamines terfenadine (fluconazole doses ≥400 mg) and astemizole is contraindicated.4 Levels of these drugs may become elevated and cause serious cardiovascular events, such as QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death.1 Although terfenadine, astemizole, and cisapride are no longer available in many countries, these contraindications may still be relevant in others. Q10.13 The azole drugs interfere to varying degrees with CYP3A4, with fluconazole also inhibiting CYP2C9. Drugs using these metabolic pathways may have drug concentrations altered when given concomitantly with an azole antifungal agent. Where significant interaction has been reported, concomitant drug levels or activities may need to be monitored and/or dose reduced, to minimize the interaction risk (see Table 10.7). Q10.14 The most notable CYP2C9 interactions with the azoles are through coadministration of fluconazole with warfarin, which can lead to significant increases in international normalized ratio (INR) values and excessive anticoagulation. When itraconazole (and to a degree fluconazole of at least 300 mg daily) and cyclosporine are given concomitantly, careful monitoring of cyclosporine concentration and serum creatinine concentration is recommended.4 Blood glucose levels may require careful monitoring when oral hypoglycemic agents are used concomitantly with azoles. Similarly, agents with narrow therapeutic windows, such as phenytoin and theophylline, may need to have careful monitoring of drug levels, as interactions secondary to azole use may more easily predispose the patient to significant AE.

Monitoring Guidelines Liver function tests should be performed in all patients before prescribing terbinafine and azoles for courses of at least 3 to 4 weeks continuously (serum transaminase tests: alanine aminotransferase [ALT], AST).5 Patients should be instructed to report any symptoms of liver dysfunction, such as persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine, or pale stools. Patients reporting such symptoms, or otherwise suspected of having hepatic dysfunction, should discontinue terbinafine and have a complete liver profile performed.5 The US package insert indicates that physicians should consider

112

PA RT I I I

Systemic Drugs for Infectious Diseases

TABLE Drug Interactions—Itraconazole and Fluconazole 10.7

Drug Category Relatively High-Risk Drug

Drug Examples Interactionsa

Comments

CYP3A4 Inhibition (itraconazole >> fluconazole unless dose over 200 mg daily)

Calcineurin inhibitors

Cyclosporine (and oral tacrolimus)

↑ drug levels and risk of severe toxicity (HBP, renal failure, hyperlipidemia and others)

Statins

Simvastatin, atorvastatin, lovastatin

same (risk myopathy, rhabdomyolysis)

Benzodiazepines

Alprazolam, triazolam, midazolam

same (risk excessive sedation)

Antipsychotics

Pimozide

same (risk QT prolongation, torsades de pointes)

Myeloperoxidase inhibitors

Dapsone

same (risk hemolysis, agranulocytosis)

Anticoagulants

Warfarin

R-enantiomer of warfarin (2nd most important substrate pathway after CYP1A2) risk bleeding

Antigout meds

Colchicine

Possible ↑ myelotoxicity

Relatively High-Risk Drug Interactionsa CYP2C9 Inhibition (primarily fluconazole) Anticoagulants

Warfarin

S-enantiomer of warfarin major substrate pathway (most important) severe risk bleeding

Statins

Fluvastatin, rosuvastatin

Statins metabolized by CYP2C9 pathway; risk myopathy, rhabdomyolysis

Antidepressants

Doxepin

Main antidepressant metabolized by CYP2C9; risk excessive sedation, QT prolongation → torsades

Anticonvulsants

Phenytoin, valproic acid

↑ drug levels and risk of severe toxicity

Lower-Risk Drug Interactions—CYP3A4 Induction (only itraconazole CYP3A4 substrate) Rifamycin antibacterials

Rifampin, rifabutin, rifapentine

CYP3A4 induction with resultant ↓ itraconazole drug levels, loss efficacy; this effect begins 1–2 wk

Aromatic anticonvulsants

Phenytoin, carbamazepine, phenobarbital

same (also nonaromatics, such as primidone, ethosuximide)

Antifungals

Griseofulvin

Weak CYP3A4 inducer

Lower-Risk Drug Interactions—CYP3A4 Inhibition (itraconazole >> fluconazole unless dose over 200 mg daily) H1 antihistamines

Fexofenadine, loratadine

Primary antihistamines (1st or 2nd generation), which are CYP3A4 substrates; historically, terfenadine, astemizole (both off the market) induced torsades de pointes in combination CYP3A4 inhibitors)

Hormonal

Estrogens, combined oral contraceptives

In general, modest risk (conceptually venous thromboembolism risk; likely a stronger genetic risk)

Retinoids

Isotretinoin (possible acitretin)

In general, modest risk (most of very few interactions other mechanisms)

Lower-Risk Drug Interactions—CYP2C9 Inhibition (primarily fluconazole) Antibacterials

Sulfonamides

In general, modest risk (likely genetic factors > dose with SJS/TEN risk)

Statins

Pitavastatin

Statin metabolized by CYP2C9 pathway to a smaller extent; risk myopathy, rhabdomyolysis

NSAID

Diclofenac, ibuprofen, piroxicam

In general, modest risk (conceptually ↑ risk GI and renal AE/SAE)

aOverall highest-risk drug interactions indicated in bold italics. AE/SAE; Adverse effects/serious adverse effects; CYP, cytochrome P-450; GI, gastrointestinal; HBP, high blood pressure; SJS/TEN, Stevens–Johnson syndrome/toxic epidermal necrolysis. The dramatic increase in number of drug interactions in medicine requires some degree of selectivity in these tables (common usage, relative risk, focus on outpatient rx)

Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. (http://www.hanstenandhorn.com/).

CHAPTER 10

monitoring complete blood counts in patients with known or suspected immunodeficiency, who are administered oral terbinafine for longer than 6 weeks.5 Q10.11 Patients should also be instructed to report taste disturbance, depression symptoms, and progressive rash.5 When giving azoles, LFT monitoring should be considered for any subject.1 LFT should be done for any subject with preexisting hepatic function abnormalities, or any subject with previous experience of liver toxicity with other medications.1 During prolonged griseofulvin therapy, periodic assessment of renal, hepatic, and hematopoietic functions should be performed.9

Conclusion Systemic oral antifungal agents have widespread use in dermatology. Dosing and efficacy vary with specific indications. Clinical use has demonstrated the general safety of oral antifungal use. However, possible risks exist for each agent, and careful monitoring of the patient should be undertaken regardless of agent used.

Bibliography: Important Reviews and Chapters Antifungal drug therapy overviews Girmenia C. New generation azole antifungals in clinical investigation. Expert Opin Investig Drugs. 2009;18(9):1279–1295. Gupta AK, Mays RR, Versteeg SG, et  al. Tinea capitis in children: a systematic review of management. J Eur Acad Dermatol Venereol. 2018;32(12):2264–2274. Gupta AK, Versteeg SG, Shear NH. Common drug-drug interactions in antifungal treatments for superficial fungal infections. Expert Opin Drug Metab Toxicol. 2018;14(4):387–398. Kreijkamp-Kaspers S, Hawke K, Guo L, et  al. Oral antifungal medication for toenail onychomycosis. Cochrane Database Syst Rev. 2017;7:CD010031. Patel D, Castelo-Soccio LA, Rubin AI, Streicher JL. Laboratory monitoring during systemic terbinafine for pediatric onychomycosis. JAMA Dermatol. 2017;153(12):1326–1327. Schmid-Wendtner MH, Korting HC. Effective treatment for dermatophytoses of the foot: effect on restoration of depressed cell-mediated immunity. J Eur Acad Dermatol Venereol. 2007;21(8):1013–1018. Van Duyn Graham L, Elewski BE. Recent updates in oral terbinafine: its use in onychomycosis and tinea capitis in the US. Mycoses. 2011;54(6):e679–e685. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol. 2010;28(2):151–159.

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Electronic References and Product Inserts Novartis Pharmaceuticals. Lamisil (terbinafine hydrochloride) Tablets (prescribing information). January 2017. Available at https://www. pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/ Lamisil_tablets.pdf. Accessed January 17, 2019. Novartis Pharmaceuticals. Lamisil (terbinafine hydrochloride) oral granules (prescribing information); 2016. Available at https://www. pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/ Lamisil_Oral_Granules.pdf. Accessed January 17, 2019. Janssen Pharmaceuticals. Inc. Sporanox (itraconazole) capsules (prescribing information); 2018. Available at http://www.janssenlabels.com/ package-insert/product-monograph/prescribing-information/SPORANOX-Capsules-pi.pdf. Accessed January 17, 2019. Janssen Pharmaceuticals. Inc. Sporanox (itraconazole) oral solution (prescribing information); 2018. Available at http://www.janssenlabels. com/package-insert/product-monograph/prescribing-information/ SPORANOX-Oral+Solution-pi.pdf. Accessed January 17, 2019. Pfizer. Diflucan (fluconazole) Tablet (package insert); 2018. Available at http://labeling.pfizer.com/ShowLabeling.aspx?id=575. Accessed January 17, 2019.

References* 46. Baran R, Hay RJ, Garduno JI. Review of antifungal therapy, part II: treatment rationale, including specific patient populations. J Dermatolog Treat. 2008;19(3):168–175. 65. Roberts BJ, Friedlander SF. Tinea capitis: a treatment update. Pediatr Ann. 2005;34(3):191–200. 77. Gupta AK, Chaudhry M, Elewski B. Tinea corporis, tinea cruris, tinea nigra and piedra. Dermatol Clin. 2003;21(3):395–400. 78. Gupta AK, Chow M, Daniel CR, Aly R. Treatments of tinea pedis. Dermatol Clin. 2003;21(3):431–462. 87. Gupta AK, Foley KA. Antifungal treatment for pityriasis versicolor. J Fungi (Basel). 2015;1(1):13–29. 95. Gupta AK, Mays RR, Versteeg SG, Shear NH, Friedlander SF. Onychomycosis in children: safety and efficacy of antifungal agents. Pediatr Dermatol. 2018;35(5):552–559. 105. Herbrecht R, Nivoix Y, Fohrer C, et al. Management of systemic fungal infections: alternatives to itraconazole. J Antimicrob Chemother. 2005;56(suppl 1):i39–i48. 118. Wolf R, Orion E, Marcos B, Matz H. Life-threatening acute adverse cutaneous drug reactions. Clin Dermatol. 2005;23(2):171–181. 119. Hay RJ. Risk/benefit ratio of modern antifungal therapy: focus on hepatic reactions. J Am Acad Dermatol. 1993;29(1):S50–S54.

* Only a selection of references are printed here. All other references in the reference list are available online at www.expert consult.com.

Web References Pharmacology—General Pharmacokinetic Properties of the Oral Antifungals 1. Janssen Pharmaceuticals, Inc. Sporanox (itraconazole) capsules [prescribing information]. Revised May 2018. Available at http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/SPORANOX-Capsules-pi.pdf. Accessed February 19, 2019. 2. Janssen Pharmaceuticals, Inc. Sporanox (itraconazole) oral solution [prescribing information]. Revised April 2018. Available at http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/SPORANOX-Oral+Solutionpi.pdf. Accessed February 19, 2019. 3. Janssen Pharmaceuticals (Canada). Sporanox (itraconazole) capsules [product monograph]. Revised December 2018. Available at: https://www.janssen.com/canada/sites/www_janssen_com_canada/files/prod_files/live/sporanox_caps_cpm.pdf. Accessed February 19, 2019. 4. Pfizer Inc. Diflucan fluconazole tablets; fluconazole for oral suspension (prescribing information). Revised February 2019. Available at http://labeling.pfizer.com/ShowLabeling. aspx?id=575. Accessed February 19, 2019. 5. Novartis Pharmaceuticals. Lamisil (terbinafine hydrochloride) tablets [prescribing information]. Revised January 2017. Available at https://www.pharma.us.novartis.com/sites/www. pharma.us.novartis.com/files/Lamisil_tablets.pdf. Accessed February 19, 2019. 6. Novartis Pharmaceuticals. Lamisil (terbinafine hydrochloride) oral granules [prescribing information]. Revised January 2017. Available at https://www.pharma.us.novartis.com/sites/www. pharma.us.novartis.com/files/Lamisil_Oral_Granules.pdf. Accessed February 19, 2019. 7. Lin CC, Magat J, Chang R, McGlotten J, Symchowicz S. Absorption, metabolism and excretion of 14C-griseofulvin in man. J Pharmacol Exp Ther. 1973;187(2):415–422. 8. Schäfer-Korting M, Korting HC, Mutschler E. Human plasma and skin blister fluid levels of griseofulvin following a single oral dose. Eur J Clin Pharmacol. 1985;29(1):109–113. 9. Valeant Pharmaceuticals North America. Gris-PEG (griseofulvin ultramicrosize) tablets [prescribing information]. Revised April 2016. Available at https://www.accessdata.FDA.gov/ drugsatFDA_docs/label/2016/050475s057lbl.pdf. Accessed February 19, 2019. 10. Pfizer Inc. VFEND (voriconazole) tablets, oral suspension and I.V. [prescribing information]. Revised January 2019. Available at http://labeling.pfizer.com/showlabeling.aspx?id=618. Accessed February 19, 2019. 11. Merck & Co. Noxafil (posaconazole) oral suspension [prescribing information]. Revised September 2017. Available at https:// www.merck.com/product/usa/pi_circulars/n/noxafil/noxafil_ pi.pdf. Accessed February 19, 2019. 12. Merck Canada, Inc. Posanol (posaconazole) oral suspension [product monograph]. Revised July 2017. Available at https:// www.merck.ca/static/pdf/POSANOL-PM_E.pdf. Accessed January 17, 2019. 13. Janssen Pharmaceuticals. Nizoral (ketoconazole) tablets USP, 200 mg [prescribing information]; 2014. Available at https://www.accessdata.FDA.gov/drugsatFDA_docs/ label/2014/018533s041lbl.pdf. Accessed February 19, 2019. 14. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA warns that prescribing of Nizoral (ketoconazole) oral tablets for unapproved uses including skin and nail infections continues; linked to patient death. May 19, 2016. https://www.FDA.gov/Drugs/DrugSafety/ucm500597.htm. Accessed January 17, 2019.

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11

Systemic Antiviral Agents UYEN NGOC MUI, CHRISTOPHER T. HALEY AND STEPHEN K. TYRING

QUESTIONS Q11.1 What is the spectrum of dermatologic conditions that human herpes virus (HHV) infections can cause? (Pg. 115, Table 11.1) Q11.2 What are the two primary steps (one step with two parts) by which acyclovir reaches the form that inhibits viral replication (similar steps for valacyclovir and famciclovir) (Pg. 115, Fig. 11.2) Q11.3 How common is acyclovir resistance, and what are the clinical implications of this resistance? (Pgs. 118, 122) Q11.4 What is the rationale for the use of acyclovir or valacyclovir in patients with recurrent erythema multiforme, and which regimens are most effective? (Pgs. 118, 120) Q11.5 Of the three drugs for HHV infections discussed in this chapter, which two are defined as ‘prodrugs’ for another active drug? (Pgs. 119, 121) Q11.6 What advantages does valacyclovir have over acyclovir in treating herpes zoster? (Pgs. 119, 120) Q11.7 How does the bioavailability differ between acyclovir, valacyclovir, and famciclovir? How might this relate to treating

varicella-zoster virus (VZV) infections and herpes simplex virus (HSV) infections?) (Pg. 121) Q11.8 What are the most important clinical circumstances that may justify long-term antiviral suppressive therapy for recurrent HSV infections? (Pg. 122) Q11.9 What are the key points concerning the development of the VZV vaccine and the priorities for clinical use of this vaccine? (Pg. 122) Q11.10 What are the two available vaccines to prevent shingles and how are they different? (Pg. 123) Q11.11 Which human immunodeficiency virus (HIV) medications function as pharmacokinetic enhancers to boost the concentrations of other antiretroviral medications? (Pg. 124) Q11.12 Concerning vaccine development for HIV prevention, (1) what are several of the methods of development used, and (2) what is the only vaccine that has demonstrated any efficacy in clinical trials? (Pg. 124x2)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R ACIP Advisory Committee on Immunization Practices ACV Acyclovir AIDS Acquired immunodeficiency syndrome AZT Azidothymidine (same as zidovudine) CDC Centers for Disease Control and Prevention CYP Cytochrome P-450 GI Gastrointestinal FCV Famciclovir FDA US Food and Drug Administration HAART Highly active antiretroviral therapy HHV Human herpes virus HIV Human immunodeficiency virus HSV Herpes simplex virus HZ Herpes zoster

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INSTI Integrase strand transfer inhibitor MMR Measles/mumps/rubella NRTI Nucleoside reverse transcriptase inhibitor NNRTI Nonnucleoside reverse transcriptase inhibitor PHN Postherpetic neuralgia PI Protease inhibitor PPC Pregnancy prescribing category Rx Prescription or medication SJS Stevens–Johnson syndrome TEN Toxic epidermal necrolysis TK Thymidine kinase VACV Valacyclovir VZV Varicella-zoster virus

CHAPTER 11

Introduction Viral diseases in dermatology can be very frustrating to treat. Prevention strategies, such as vaccines, proper sanitation, vector control, blood testing, condom use/abstinence, and education remain essential to managing viral spread. Once viruses, such as human herpes viruses (HHV) and human immunodeficiency virus (HIV) are acquired, antiviral agents are essentially the sole method of treatment. A large number of antiviral medications have been approved by the US Food and Drug Administration (FDA) during the past 3 decades. New antiviral agents and vaccines are continuously being researched for more effective control of these viral diseases. To date, there are over 30 FDA-approved systemic antiviral drugs for treatment of infections caused by HHV and HIV, as well as for hepatitis viruses, influenza, and so on. This chapter primarily addresses the current use of systemic antiviral agents (against HHV) in dermatology, as well as new agents currently under investigation. Also provided is a brief overview of antiviral therapy for HIV infections.

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HSV-2), which most frequently produce herpes labialis (cold sores) and genital herpes, respectively; however, both types of lesion can be caused by either virus. HSV-1 and -2 have also been shown to cause gingivostomatitis, ocular disease, herpes gladiatorum, eczema herpeticum, herpetic whitlow, neonatal herpes, lumbosacral herpes, herpetic keratoconjunctivitis, herpes encephalitis, cervicitis, and erythema multiforme.1 HHV type 3 is also known as varicella-zoster virus (VZV). It is more commonly called chickenpox in its primary form and herpes zoster (HZ) or shingles in its recurrent form. The remaining members of the HHV family and resulting conditions are listed in Table 11.1. The three primary drugs that have efficacy against HSV-1, HSV-2, and VZV are acyclovir, valacyclovir, and famciclovir (Table 11.2).

Acyclovir Pharmacology

Older Nomenclature

Resultant Diseases

Acyclovir (9-2-hydroxyethoxymethyl guanine or acycloguanosine) (ACV), a guanosine analog, is the most well-known and widely used antiviral drug in the world (Fig. 11.1).2 ACV is available in intravenous, oral, and topical formulations, but its oral bioavailability is low (∼20%).3 Q11.2 Activation of ACV requires phosphorylation by herpes-specific thymidine kinase (TK) before bi- and triphosphorylation by host cellular enzymes. The active triphosphorylated ACV inhibits viral DNA polymerase by serving as an obligate chain terminator (i.e., complete and irreversible inhibition of further viral DNA synthesis) (Fig. 11.2). Furman and co-authors suggested that activated triphosphate of ACV is substantially more effective in inactivating the viral polymerase than the cellular DNA polymerase.4 Table 11.3 contains the key pharmacologic concepts for ACV.

HHV 1

Herpes simplex virus type 1 (HSV-1)

Herpes labialis, etc.

Clinical Use

HHV 2

Herpes simplex virus type 2 (HSV-2)

Genital herpes, etc.

HHV 3

Varicella-zoster virus (VZV)

Chicken pox, HZ

HHV 4

Epstein-Barr virus (EBV)

Mononucleosis, Burkitt lymphoma

HHV 5

Cytomegalovirus (CMV)

CMV retinitis

HHV 6

No specific name

Roseola infantum, etc.

HHV 7

No specific name

Roseola infantum, Pityriasis roseaa, etc.

HHV 8

Kaposi sarcoma herpes virus

Kaposi sarcoma (classic and epidemic)

Drugs for Human Herpes Virus Infections HHV are double-stranded, linear deoxyribonucleic acid (DNA) viruses that cause a variety of illnesses. Q11.1 The HHV family includes herpes simplex virus type 1 and type 2 (HSV-1 and TABLE Human Herpes Viruses 11.1

Hhv Number

aThe

causal role of HHV 7 in pityriasis rosea has not been fully established. HZ, Herpes zoster.

Indications for ACV are found in Box 11.1.1,3,5–19 Box 11.2 details various risks of ACV. US Food and Drug Administration-Approved Indications Herpes Simplex Virus Infections. ACV can be administered

topically, orally, and intravenously. The oral form is the most widely used for HSV infections. In the therapy of genital HSV, oral ACV is indicated for treatment of the initial episode and recurrent disease, as well as for suppressive therapy. For first-episode genital HSV, the original recommended dose was 200 mg 5 times daily for 10 days. Although ACV has greater efficacy when used for first-episode genital HSV, it also shows significant benefit in recurrent disease if therapy is initiated during the prodromal phase. For recurrent genital HSV, originally ACV was dosed as 200 mg 5 times daily for 5 days. Far more commonly, clinicians use ACV dosed as 400 mg 3 times daily (TID) for 10 days (first-episode HSV) or 5 days (HSV recurrences). The decreased frequency leads to greater convenience and increased patient compliance. Suppressive therapy is recommended for frequent recurrences. Continuous suppressive therapy with ACV 400 mg twice daily reduces

TABLE Systemic Antiviral Agents Used To Treat Human Herpes Virus Infections 11.2

Generic Name

Trade Name

Generic Available

Tablet Size

Oral Suspensions

Topical Preparation

Acyclovir

Zovirax

Yes

200, 400, 800 mg

Yes

Yes

Valacyclovir

Valtrex

Yes

500, 1000 mg

No

No

Famciclovir

Famvir

Yes

125, 250, 500 mg

No

No

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recurrence of genital HSV by 80% to 90%, and reduces asymptomatic viral shedding of HSV-2 by 95%.5 Suppressive ACV in pregnant females beginning before 36 weeks’ gestation reduces the risk of perinatal transmission, viral shedding, and the number of caesarean deliveries.6 ACV is also beneficial in recurrent orofacial HSV (herpes labialis). ACV 200 mg 5 times daily for 5 days expedites crusting, but does not appear to reduce healing time significantly. Maximal therapeutic benefits are seen when therapy is initiated during the prodromal stages before vesicle formation. Suppressive therapy should be considered for patients with severe or frequent recurrences defined as six or more episodes per year or those with a history of ocular HSV disease.7,8 This guideline no doubt has flexibility based on individual patient circumstances. ACV suppressive therapy following initial ocular herpes has been shown to reduce the recurrence by 45% in the first year.7 Topical ACV is also promoted for the treatment of orofacial HSV. Although it has been suggested that topical ACV has limited efficacy because of

inadequate penetration of the drug through the stratum corneum, recent data demonstrate transdermal penetration of ACV can be enhanced by using different vehicles, percutaneous absorption enhancers (such as collagen microparticles, oleic acid, nonionic surfactants to name a few), and iontophoresis.3 Intravenous ACV is reserved for severe illness and in the immunocompromised because of its markedly greater bioavailability (∼100%).1 Indications include disseminated HSV disease, complicated primary infection, neonatal infection, eczema herpeticum, herpes encephalitis, and other HSV subsets that fails oral therapy. Several randomized, placebo-controlled trials have found ACV suppressive therapy among people dually infected with HSV-2 and HIV-1 to reduce risk of HIV-1 progression and slowed CD4 cell count falling to less than 350 cells per µL.9,10 The effect of ACV on the clinical course of HIV is mediated through decreases in HIV viral load, the primary determinant of HIV disease progression, and via suppression of HSV-2-mediated inflammation.11 O N

HN

H 2N

N

N

O N

HN

O O

H2 N

N

N

O O Famciclovir

O

O H N H Valacyclovir

O N

HN

H2N

N

N

O

Acyclovir OH

• Fig. 11.1

Acyclovir, valacyclovir, famciclovir.

O

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Valacyclovir

Systemic Antiviral Agents

Famciclovir A

A

Penciclovir

Acyclovir

B

Viral-thymidine kinase

Acyclovir (or penciclovir) monophosphate

C

Cellular-GMP kinase Cellular-other kinases

Acyclovir (or penciclovir) triphosphate D

Deoxy guanosine triphosphate

Competitive inhibition

Viral-DNA polymerase

Incorporation of acyclovir (or penciclovir) triphosphate into DNA E DNA chain termination A Valacyclovir and famciclovir are prodrugs, which must be converted their respective active drug forms acyclovir and penciclovir. B Viral thymidine kinase converts these active drug forms to either acyclovir monophosphate or penciclovir monophosphate. C Cellular (human) GMP kinase and other cellular kinases convert the monophosphate form to either acyclovir triphosphate or penciclovir triphosphate. D Acyclovir (or penciclovir) triphosphate competes with normal deoxyguanosine triphosphate for the enzyme (viral) DNA polymerase; these drug triphosphate forms are much less inhibitory of human DNA polymerase. E The incorporation of acyclovir (or penciclovir) triphosphate into DNA leads to chain termination, with resultant viral replication.

• Fig. 11.2

Antiviral drug mechanism. DNA, Deoxyribonucleic acid; GMP, guanosine monophosphate.

TABLE Key Pharmacologic Concepts 11.3

Peak Levels

Bioavailability (%)

Protein Binding (%)

Acyclovir

1.5–2.0 hours

15–30

Valacyclovir

Uncertain

Famciclovir

0.9 hours

Drug Name

Half-Life

Metabolism

Excretion

9–33

1.3–1.5 hours

No hepatic microsomal metabolism

Roughly equal urine and fecal

54.50

13.5–17.9

2.5–3.3 hours

No hepatic microsomal metabolism; conversion to acyclovir

Roughly equal urine and fecal

77

cellular function; cellular immunity > humoral immunity; major portion of effects mediated via above cytokine alterations.

Vascular Effects Angiogenesis

↓ Angiogenesis in wound healing and with proliferative lesions (hemangiomas).

Vasoconstriction

Net result of vasocortin and vasoregulin, potentiate response to catecholamines.

Decreased permeability

Decreased vascular smooth muscle response to histamine and bradykinin.

AP-1; Activating protein-1; CS, corticosteroid; HETE, hydroxyeicosatetraenoic acid; IFN, interferon; IκB, inhibitor kappa B; IL, interleukin; NFκB, nuclear factor kappa B; PMN, polymorphonuclear cell; TNF, tumor necrosis factor; WBC, white blood cell.

CHAPTER 13

reader should take sufficient time to thoroughly understand these two tables in order to have a broad understanding of the overall benefits and risks of systemic CS. There will next be a concise discussion on normal HPA-axis function, glucocorticoid effects, and MC effects. This section concludes with relatively new information on glucocorticoid receptors (GCR), CS resistance and tachyphylaxis, transcription factors, and apoptosis. The reader is encouraged to pursue reviews concerning newer scientific data on the CS mechanisms of action.10,11 Normal Hypothalamic-Pituitary-Adrenal-Axis Function. It is important to understand the normal function of the HPA axis in order to better understand the potential for HPA-axis suppression by synthetic CS. For further background information, several reviews are particularly helpful.12–17 The primary stimulus for release of endogenous cortisol originates in the hypothalamus. The tropic hormone is known as corticotropin-releasing factor (CRF). ACTH is subsequently released by the anterior pituitary. ACTH is produced from the prohormone pro-ACTH/endorphin. There are approximately 10 bursts of ACTH release throughout the day. The greatest frequency of these bursts occurs in the early morning hours during a normal sleep cycle. The zona fasciculata of the adrenal cortex is then stimulated to produce and release cortisol. ACTH also stimulates adrenal androgen synthesis. However, ACTH is not significantly involved in the release of the MC aldosterone. There are three main controls of endogenous cortisol production. These are discussed in the summary ‘HPA axis in a nutshell’ (Box 13.2). Glucocorticoid Effects (Table 13.3). CS plays an important teleologic role in maintaining adequate blood glucose levels for brain function.5 Gluconeogenesis generates glucose at the expense of amino acids derived from endogenous proteins. CS also produces peripheral insulin resistance, which impedes glucose absorption by various body tissues. In addition, glycogen storage in the liver is enhanced. Lipid stores are stimulated to undergo lipolysis, generating increased amounts of triglycerides from which to derive energy. The net effect is a catabolic state that produces carbohydrates at the expense of protein and fat stores.5 Through gluconeogenesis, proteins from muscle, trabecular bone (especially vertebral and hip), dermal connective tissue, and vascular proteins are metabolized. Lipolysis results in triglyceride release, with additional fat redistribution (lipodystrophy) to body sites that are characteristic of the habitus for Cushing syndrome. Mineralocorticoid Effects. Aldosterone is the primary endogenous MC hormone. The primary aldosterone effect is sodium reabsorption and resultant water reabsorption at the proximal tubule site in the kidneys. Sodium is exchanged for potassium, which leads to hypokalemia when there is excessive MC effect. ACTH has no direct control on MC production. The primary MC control mechanisms are through the renin–angiotensin system and serum potassium levels.12,14 CS with significant MC effects (such as hydrocortisone) have a similar effect on sodium, potassium, and fluid balance as aldosterone (Table 13.3). Longacting CS (such as dexamethasone and betamethasone) have essentially no MC effect (see Table 13.1). Glucocorticoid Receptor Physiology and Corticosteroid Resistance. There is only one GCR, but a diverse collection of isoforms,

which accounts for endogenous glucocorticoid effects as well as the pharmacological effects of synthetic CS (resulting in both beneficial and AE).18,19 This cytosolic receptor is expressed throughout

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tissues, but there is considerable heterogeneity in sensitivity and biological responses. The GCR functions directly as a transcription factor, which upon translocation to the nucleus binds directly to various glucocorticoid responsive elements of multiple genes in DNA. In addition, the ligand–GCR complex can activate other transcription factors, as detailed in the next section. CS exerts its effects through both genomic and nongenomic actions. Splice variants, translational isoforms, posttranslational modifications, and polymorphisms give a molecular basis for sensitivity of glucocorticoid responsiveness. There are rare cases of hereditary glucocorticoid resistance, in which there are mutations in the GCR gene.20 In clinical practice, relative resistance at the GCR in otherwise healthy individuals is much more common than previously recognized. In addition, relative resistance is because of altered CS bioavailability, altered ligand binding to GCR, or altered translocation of the activated GCR complex to the nucleus.21 Conceptually, this resistance could represent a negative feedback system of sorts, with downregulation of GCR after prolonged or high-dose CS therapy. Corticosteroids and Transcription Factors. There are two welldescribed transcription factors with a central role in amplification of the inflammatory response (Fig. 13.2). These transcription factors are nuclear factor kappa B (NFκB) and AP-1. NFκB is biologically inactive as long as it is bound to inhibitor kappa B (IκB).22,23 Free NFκB translocates to the nucleus, where it induces transcription of numerous cytokines including (1) ‘immunoawakening’ cytokines (interleukin [IL]-1β, tumor necrosis factor • BOX 13.2 Hypothalamic-Pituitary-Adrenal Axis in a

Nutshell10,12–14 Components of Hypothalamic-Pituitary-Adrenal (HPA) Axis and Hormone Produced Hypothalamus—corticotrophin-releasing factor (CRF) Pituitary (anterior)—adrenocorticotropic hormone (ACTH) Adrenal—cortisol (same as hydrocortisone)

Basal and Stress Levels of Corticosteroid (CS) Production Basal production of cortisol—20–30 mg daily Basal production in prednisone equivalents—5–7.5 mg daily Maximal stress production of cortisol—300 mg daily Maximal stress production in prednisone equivalents—75 mg daily ‘Minor stress’ production of cortisol—probably two to three times basal production

Response of Various Components to Exogenous CS and Subsequent ‘Stress’ Hypothalamus—first to be suppressed, first to recover full function; is most critical component for adequate stress responsiveness Adrenal—slower to be suppressed, much slower to recover full function

Regulatory Mechanisms and Sources of Variability Circadian variations—CRF (and thus ACTH) have innate diurnal variations tied to sleep cycle (highest production mid-sleep, lowest late afternoon) Negative feedback—increased cortisol levels reduce CRF and ACTH production Stress response—increased CRF release and subsequently ACTH release

Back-Up Mechanisms for CS Production in Setting of Adrenal Insufficiency CRF alternate sites of production—cerebral cortex and limbic system, which can be released by acetylcholine and serotonin Alternative inducers of ACTH release—catecholamines, vasopressin All the above means serve to maintain glucose homeostasis ACTH has no role in endogenous mineralocorticoid production.

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TABLE Physiologic Glucocorticoid and Mineralocorticoid Effects5,10,18,19 13.3

Glucocorticoid Effectsa

MC Effectsb

Glucose Metabolism

Aldosterone Effects—Endogenous

Gluconeogenesis at expense of protein catabolism

Major effect is sodium and water retention

Peripheral insulin resistance—reduced glucose entry into cells

This effect is primarily at proximal tubule in kidney

Glycogen storage in liver

Potassium is excreted in exchange sodium at this site

Lipid Metabolism

Corticosteroid Effects—Exogenous

Lipolysis releasing triglycerides as source of ‘energy’

Endogenous/exogenous cortisol significant MC effects

Fat redistribution to central locations

See Table 13.1 for MC effect of various CS

Regulation Of Above Processes

Regulation of Endogenous Aldosterone

ACTH (pituitary) induces release of cortisol (adrenal)

ACTH has no role in aldosterone production

Negative feedback loop to hypothalamus (site of CRF production)

Regulation primarily by renin–angiotensin, potassium

aConceptually, all

the glucocorticoid effects are prioritized to maintain brain glucose homeostasis. priority for MC is to maintain sodium and fluid homeostasis, including a normal blood pressure. ACTH, Adrenocorticotropic hormone; CRF, corticotropin-releasing factor; CS, corticosteroid; MC, mineralocorticoid. bMajor

“Activation signals” B IκB kinase A (NFκΒ/ΙκΒ)

E Corticosteroids

D C

NFκB-free (active)

Especially IL-Iβ and TNF-α

(Direct binding) F Various proinflammatory cytokines, adhesion molecules Release from cell

A “Normally” NFκB is bound by IκB (inhibitor κB) and rendered inactive as a transcription factor. B Many “activation signals” (see text) which incite an inflammatory response lead to production of IkB kinases, resulting in free (active) NFκB. C The free form of NFκB serves as a transcription factor for a multitude of proinflammatory cytokines and adhesion molecules (see text). D Among the cytokines produced are IL-1α and TNF-α which form a (+) feedback loop further stimulating release of free NFκB. E Corticosteroids production of IκB, resulting in free NFκB. F Corticosteroids also directly bind to free NFkB, inhibiting the transcription factor.

• Fig. 13.2 Nuclear factor kappa B (NFκB) transcription factor and corticosteroids. IL, Interleukin; IκB, inhibitor kappa B; TNF, tumor necrosis factor. [TNF]-α), (2) ‘immunomodulatory’ cytokines (IL-2, IL-8), (3) growth factors, (granulocyte-colony stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]), (4) adhesion molecules (intercellular adhesion molecule 1 [ICAM1], E-selectin), (5) receptors (IL-2 receptor), and (6) proinflammatory enzymes (cyclooxygenase-2 [COX-2], phospholipase A2).22 CS reduce the effects of NFκB in two ways.22,23 The CS-GCR complex leads to increased IκB formation, leading to subsequent

NFκB binding by this inhibitory protein. The GCR/CS complex can also directly bind to NFκB, thus inhibiting this transcription factor. By either means, there can be a dramatic reduction of a wide variety of components of the inflammatory response via this mechanism of CS. AP-1 consists of either c-jun homodimers or c-jun/c-fos heterodimers, which bind to a common deoxyribonucleic acid (DNA) site, the AP-1 binding site.10,24 There is tremendous overlap with the inflammatory response genes induced by AP-1 and NFκB.25

CHAPTER 13

In general, transrepression by GCR/CS complex of proinflammatory cytokines (such as IL-1β, TNF-α, interferon regulatory factor 3 [IRF-3]) accounts for most of anti-inflammatory effects of CS. IRF-3 is a member of the interferon regulatory transcription factor family and plays an important role in the innate immune system. In contrast, transactivation by the GCR/CS complex of various regulatory proteins is responsible for most CS AE (such as diabetes, glaucoma). As such, selective glucocorticoid receptor agonist(s) (SEGRA) that favor transrepression were developed as therapeutic agents with reduced AE. However, more recent data show that the transactivation potential of GR is indispensable for its anti-inflammatory properties.26 Corticosteroid-Induced Apoptosis. Apoptosis is an orderly process of programmed cell death. The process is a biologically active, noninflammatory sequence of cellular changes that occur with an intact plasma membrane despite nuclear fragmentation. Q13.3 CS can directly induce apoptosis in lymphocytes and eosinophils.27 CS can induce apoptosis at least in part through downregulation of the CD3 molecule of T cells; this molecule plays an important role in T-cell activation.28 There can also be an indirect effect on lymphocytes and eosinophils through CS-induced suppression of cytokines essential to cellular survival.27 The logical application of these facts is an underlying explanation for CS effects in autoimmune disorders (apoptosis of autoreactive T cells), allergic disorders (apoptosis of eosinophils), and certain neoplastic disorders (apoptosis of malignant T cells). It is doubtful that the ability of CS to induce apoptosis is limited to these cell types.

Clinical Use Food and Drug Administation-Approved Indications and Off-Label Dermatologic Uses Q13.3 Many of the common CS-responsive dermatoses are listed in Box 13.3. A few disorders are discussed selectively to illustrate various principles of CS therapy. Reference citations for many other dermatoses not discussed specifically in the text are listed in Box 13.3 as well. Overall, well-controlled studies of CS use in the following dermatoses are quite uncommon. In clinical practice, it is actually quite easy in most cases to have a relatively high level of certainty about the benefits of CS in an individual patient through tapering the dose (the disease flares) and cautiously raising the dose (disease control returns). Definitions of importance to both the Clinical Use and Therapeutic Guidelines sections are listed in Table 13.4. Pemphigus Vulgaris. The best-studied purely dermatologic indication for systemic CS therapy is pemphigus vulgaris. The emphasis here is high-dose CS therapy, with use of adjunctive ‘steroid-sparing’ immunosuppressive therapy. CS are appropriate at the start of therapy for any relatively severe case of pemphigus vulgaris that has no absolute contraindications to CS use. Adjunctive therapy is generally used with a choice of azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, cyclophosphamide, rituximab, intravenous immune globulin (IVIg), or plasmapheresis.29–33 Anti-inflammatory antibiotics, such as the tetracyclines, as well as CS-sparing immunosuppressive medications have been used for milder cases of pemphigus vulgaris and for pemphigus foliaceus. Pulse methylprednisolone as well as rituximab are other options, which may be indicated to attain rapid disease control in more severe cases of pemphigus vulgaris. Current management includes prednisone doses no greater than 2 mg/kg daily in divided doses. In general, it is reasonable to start prednisone at 1 to 1.5 mg/kg daily, increasing to the above dose

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• BOX 13.3 Systemic Corticosteroid Indications Bullous Dermatoses Pemphigus vulgaris/superficial formsa 29–37 Bullous pemphigoida 38–43 Mucous membrane/cicatricial pemphigoid123–125 Herpes gestationis126,127 Epidermolysis bullosa acquisita128 Linear IgA bullous dermatosis129,130 Stevens–Johnson syndrome/TENa 44–53 Erythema multiforme majora

Autoimmune Connective Tissue Diseases Lupus erythematosus131–133 (systemica) Dermatomyositisa 134–138 Systemic sclerosis or diffuse morphea Eosinophilic fasciitis Mixed connective tissue disease Relapsing polychondritis

Vasculitis Cutaneous139–141 Systemic142–145

Neutrophilic Dermatoses Pyoderma gangrenosum146–152 Behçet disease/aphthous ulcers153–155 Sweet syndrome156,157

Dermatitis/Papulosquamous Dermatoses Contact dermatitis54 Atopic dermatitis55 Exfoliative erythroderma56 Lichen planus158–162

Other Dermatoses DRESS syndrome Sarcoidosis163–165 Sunburn166 or photodermatitis Urticaria (severea)167 Androgen excess (acne/hirsutism)57,58 Prevention of isotretinoin-induced acne fulminans aUS

Food and Drug Administration-approved indications. DRESS, Drug reaction with eosinophilia and systemic symptoms.

range very selectively as indicated for more severe cases of pemphigus vulgaris. Disease control is usually attained by 4 to 6 weeks. Given this adequate disease control, the divided dose should be consolidated into a single daily dose and tapered rapidly to the 40-mg daily range. Azathioprine or related immunosuppressive drugs can be added at the time of prednisone tapering in many cases. For more severe cases it is wise to add the ‘CS-sparing’ agent at the start of therapy. Management of oral involvement needs to be reasonably aggressive, both to limit progression to more serious cutaneous involvement and to maintain adequate fluid and nutrition intake.34 Juvenile pemphigus vulgaris is overall similar to that just described, with CS doses adjusted for body weight.35,36 The challenge of managing paraneoplastic pemphigus has been reviewed by Anhalt.37 Bullous Pemphigoid. In patients with bullous pemphigoid, moderate doses of CS up to 1 mg/kg daily are used.38 The CS course is typically given for a defined duration of time (generally 3–6 months or less), ideally achieving a physiologic dose range within 1 to 2 months. Nonsteroidal immunosuppressive drugs

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TABLE Some Definitions Used in This Chapter Pertaining To Corticosteroid Therapy 13.4

Dosing Level Definitions Decrement

Amount of reduction in CS dose—either a fixed percentage or fixed interval decrease

Increment

Amount of increase in CS dose, guided by the urgency to attain disease control

Induction

Initial CS dose focused on quickly attaining disease control

Maintenance

Relatively constant dose of CS to maintain disease control attained by induction dose

Minimal effective

The lowest dose of CS just adequate to almost completely control the disease process

Pharmacologic

Generally considered to be any dose above physiologic levels (see text)

Physiologic

Dose of exogenous CS which is similar to the quantity of endogenous CS produced

Replacement

Is a synonym of physiologic dose—term also used to refer to endogenous MC levels

Supraphysiologic

Is a synonym of pharmacologic dose

Tapering

Any effort to reduce the CS dose, given that reasonable disease control is attained

Dosing Frequency or Duration Definitions Alternate-day

CS doses given every other day—result is an ‘on’ day and an ‘off’ day

Burst

Short course of CS (generally 2–3 weeks or less) to control self-limited disease

Consolidation

Change from a divided dose to a single daily dose without changing the daily dose; necessary step before tapering

Divided

Any dosing frequency which is more frequent than daily dosing; usually BID or QID

‘Off’ day

With alternate-day therapy, day in which CS is omitted (or lower dose is given)

‘On’ day

With alternate-day therapy, day in which CS is administered (or higher dose is given)

Pulse

Usually represents a very brief course (5–7 days) of very high dose (10–15 mg/kg per day) of intravenous methylprednisolone (see text for other usage of this term)

CS, Corticosteroid; MC, mineralocorticoid.

(‘CS-sparing’ drugs) should be the mainstay of therapy if the disease persists beyond this time. As with most indications for systemic CS, randomized controlled trials are few in number.39 One such trial noted that topical CS was overall equivalent to systemic CS for patients with bullous pemphigoid.40 It is indeed counterintuitive that patients with widespread intact blisters could benefit from topical CS alone: experience dictates that systemic CS and appropriate ‘CS-sparing’ measures are still of central importance in this setting.41 In general, 60 to 80 mg daily (∼1 mg/kg daily) of prednisone in divided doses is successful in eliminating new blister formation within several weeks. Should the patient not respond to this dose, or require a high maintenance dose, adjunctive immunosuppressive therapy can be added. In the absence of new blisters over 5 to 7 days, the prednisone dose can be gradually tapered. Contrary to prior reports, Schmidt and coworkers reported that disease activity can be successfully monitored by following bullous pemphigoid antigen (BPAg2) 180 titers.42 Deaths still occasionally occur in older patients with more extensive involvement; more conservative management using alternatives to CS may help lessen the risk of sepsis in this age group.43 Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis. There is still significant controversy regarding the use of sys-

temic CS for the spectrum of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Trends toward the use of cyclosporine for these patients has taken some of the heat off the debate. A recent meta-analysis and review of 96 studies found CS and cyclosporine were the most promising systemic immunomodulating therapies for SJS/TEN, although all analyses had limitations.44 A significant number of studies support routine CS

therapy.45–47 A majority of studies, however, present data supporting routine use of burn unit care in the absence of systemic CS therapy.48–52 These studies report a higher fatality rate, particularly from sepsis, in CS-treated patients, than in patients managed in a burn unit without CS therapy. Proponents of routine systemic CS use suggest that for SJS and TEN patients, systemic CS treatment early in the disease course (before significant sloughing of skin), followed by rapid tapering of CS, may be beneficial and even life saving.53 After widespread sloughing occurs (>10% of total surface area), the risk of infection clearly outweighs the potential CS benefits. Of importance is that drug and infectious precipitators be sought and eliminated if possible. Should CS therapy be indicated, up to 2 to 2.5 mg/kg daily of IV methylprednisolone in divided doses is generally used initially, with relatively rapid tapering to more moderate doses when new blister formation ceases. Acute Dermatitis. Severe acute contact dermatitis caused by poison ivy/poison oak is a classic situation in which a 2- to 3-week burst of systemic CS therapy is usually successful at minimal risk to the patient.54 The potential for ‘rebound’ disease activity as a result of prednisone courses of less than 10 to 14 days is important to consider. Cases with widespread cutaneous involvement (or significant facial involvement) treated early in their course typically respond rapidly. Doses up to 1 mg/kg prednisone daily (generally 40–60 mg daily) tapered over 2 to 3 weeks yield adequate improvement with minimal risk of rebound flare after cessation of therapy. A simple approach that is easy for patients to follow uses just 20 mg prednisone tablets. The patient receives 5 days

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141

TABLE Comparison of Oral Versus Intramuscular Corticosteroid Administration19,61,62 13.5

Issue

Oral Administration

Intramuscular Administration

Absorption

Reasonably predictable

Highly variable from patient to patient

Compliance

Variable based on patient reliability

Guaranteed that dose is administered

Duration of therapy

Any duration possible

Must use short-, intermediate-, and long-acting IM versions

Patient illness affecting dosing

Requires ‘cooperative’ GI tract

Can be given with nausea/vomiting

Patient participation in dosing

Requires active patient participation

Patient in a passive role

Physician level of control

Can vary the doses based on disease activity and adverse effects

Can be certain the patient received the medication

Reproduces diurnal variation

With a.m. dosing reproduces diurnal variation somewhat

Constant levels without diurnal variance

Tapering

Precise tapering possible

Gradual tapering as drug metabolized

GI, Gastrointestinal; IM, intramuscular.

each of 60, 40, and 20 mg of prednisone. Various ‘dose packs’ of prednisone and methylprednisolone typically do not provide an adequate dose (to rapidly attain disease control) for an adequate duration (to avoid a rebound flare). Acute flares of chronic atopic, nummular, or contact dermatitis can be managed in a similar fashion, although a recent systematic review did not find evidence strong enough to determine optimal delivery or duration of systemic CS in atopic dermatitis and discouraged their use because of short- and long-term AE and an unfavorable risk–benefit profile.55 Because of rebound flaring, use of CS should ideally be limited to short courses as a bridge to CS-sparing agents. Maintenance CS therapy is best avoided in these settings. Doses of prednisone significantly less than 1mg/kg daily will commonly suffice for acute flares of chronic dermatitis subsets. Exfoliative Erythroderma. Exfoliative erythroderma management commonly requires systemic CS therapy.56 Given that psoriasis has been excluded, exfoliative erythroderma refractory to aggressive topical management or to phototherapy may respond to prednisone up to 1 mg/kg daily. This dose is tapered rapidly to low-dose alternate-day therapy. In erythroderma patients, a lowdose daily or alternate-day therapy at or near physiologic levels for an additional 2 to 3 weeks may be required for patients to normalize the epidermal barrier function. Androgen Excess Syndromes. Q13.4 For hirsutism and recalcitrant acne vulgaris due to elevated adrenal androgens (most commonly mild dehydroepiandrosterone-sulfate [DHEA-S] elevations), a unique CS approach is often indicated. In these patients, night-time suppressive therapy with low-dose dexamethasone (below physiologic dose levels) is predictably successful. Most cases can be controlled with 0.125 to 0.375 mg of dexamethasone at bedtime.57,58 This timing is important to suppress the early morning peak of ACTH, which stimulates adrenal androgen production. A reasonable approach is to start with dexamethasone 0.125 mg nightly, with the repeat androgen laboratory test in 6 to 8 weeks. If the test result has not normalized, dose increases of 0.125 mg up to a maximum of 0.375 mg may be used, with follow-up DHEA-S 6 to 8 weeks after dose increments. For a more complete discussion on androgen excess syndromes, see Chapter 34. Additionally, short-term CS therapy can be considered to prevent acne

fulminans from flaring during initiation of isotretinoin for treatment of severe nodulocystic acne. Herpes Zoster/Postherpetic Neuralgia. Another controversial area of systemic CS therapy is prevention of postherpetic neuralgia. A 2013 Cochrane review concluded that systemic CS is beneficial in treating acute pain related to herpes zoster infection, but does not prevent postherpetic neuralgia.59 It is reasonable to treat (1) patients with facial involvement, (2) patients with severe acute pain during the cutaneous eruption, and (3) patients over 55 to 60 years of age, using combined antiviral and CS therapy, ideally initially very early in the disease course. Although disseminated herpes zoster from CS therapy is a theoretical concern, this is a distinctly uncommon complication in patients with normal baseline immunity and simultaneous antiviral therapy. Recent evidence suggests that systemic CS may have a greater role in treating the acute pain of herpes zoster than for preventing postherpetic neuralgia.60

Intramuscular Corticosteroid Administration Background Issues. Q13.5 Dermatologists have long held widely divergent viewpoints regarding the pros and cons of IM CS therapy. Table 13.5 attempts to summarize both sides of the ‘argument.’ In addition, the relatively unique complications of IM CS are listed in Box 13.4. Hypothalamic-Pituitary-Adrenal-Axis Suppression. A pivotal point of debate is the effect of IM CS on the HPA axis. Kusama and associates detected HPA-axis suppression up to 3 to 4 weeks after each injection of triamcinolone acetonide, as measured by plasma cortisol and urine 17-hydroxycorticosteroids.61 Mikhail and colleagues studied patients receiving IM triamcinolone acetonide every 6 weeks for 1.5 to 5 years.62 Roughly half the patients had impaired response to the insulin hypoglycemia test. The authors noted that the interval between doses is a more important factor in HPA-axis suppression than the actual dose administered. Lowdose IM CS at 2 to 4-week intervals produced greater suppression than did higher doses at 6-week intervals. Using the metyrapone test, Carson and associates found evidence of HPA-axis suppression up to 10 months after treatment.63 Droszcz and colleagues detected abnormal ACTH stimulation in 6 of 48 patients (13%)

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• BOX 13.4 Complications Relatively Unique to

Intramuscular Corticosteroids61–62,118 Injection Site Complications Cold abscess Subcutaneous fat atrophy Crystal deposition

Other Adverse Effects Menstrual irregularities Purpura (incidence appears to be increased)

receiving IM triamcinolone acetonide every 2 to 6 weeks.64 In a related study, Carson and associates evaluated triamcinolone acetonide 40 mg given every 3 weeks for four doses.63 This resulted in anovulatory menstrual cycles in women because of decreased gonadotropin levels. Traditionally it has been taught that CSinduced menstrual abnormalities were generally due to IM CS. More recently, relatively small studies have demonstrated that up to 40% of premenopausal women on at least 20 mg prednisone daily experience significant menstrual abnormalities.65 General Dosing Strategies. After the arguments and data just given, a reasonably balanced viewpoint follows. Serious AE are rare with either a single IM CS injection or a burst of oral prednisone. Rarely do oral ‘bursts,’ single IM injections, or long-term use of either route of administration result in clinically relevant, significant HPA-axis suppression with CS use for dermatologic indications. Neither route of administration has a clear-cut advantage in withdrawal from chronic CS use. It is important to focus on altering disease precipitators and providing adequately aggressive topical therapy when either oral or IM CS are given. Should repeated IM CS therapy be desired by clinicians, shortto intermediate-acting products such as Celestone and Aristocort should be used. When a long-acting form such as Kenalog is used, a reasonable limit would be three to four injections per year. Each clinician must make up his or her own mind concerning the relative advantages and disadvantages of IM versus oral CS therapy. As is often the case, the correct answer depends on the clinical situation; neither form has a clear-cut advantage over the other. In general, the authors favors the precision of dosing and the active patient participation that oral CS regimens require for most dermatoses. Given the very thick stratum corneum on the palms (and soles) and the general challenge of successfully treating various subsets of hand dermatitis topically, our most common use of IM CS is for these patients (Kenalog 80 mg IM ideally three to four times yearly at most, ideally tapering to one to two injections yearly over time).

Pulse Intravenous Corticosteroid Administration General Philosophy and Dosing Strategies. Pulse CS therapy has been proposed as a means to rapidly control life-threatening or serious conditions with minimal toxicity, allowing for less aggressive long-term maintenance CS therapy. Typically, 500 to 1000 mg of methylprednisolone (roughly 10–15 mg/kg daily) is given IV over at least 60 minutes. This dose is repeated on a daily basis for 3 to 5 consecutive days. Pulse methylprednisolone is traditionally administered in an inpatient setting, with cardiac and

electrolyte monitoring highly recommended. Alternate-day CS or a nonsteroidal immunosuppressive (‘CS-sparing’) drug such azathioprine and cyclosporine is used to maintain the improvement from the pulse IV CS. Risks of Pulse Intravenous Corticosteroid. Sudden death of presumed cardiac origin is a notable complication of IV pulse CS therapy.66,67 Atrial fibrillation has been reported as well.68 Furthermore, anaphylaxis attributed to pulse IV CS is a potentially life-threatening complication.69 Acute electrolyte shifts have been postulated to explain the rare cases of sudden cardiac death.66,67 Careful potassium infusions may minimize the risk of these potentially serious cardiac AE.70 Given that the vast majority of cardiac complications have occurred outside of dermatologic settings, some authors have questioned the need for hospitalization and cardiac monitoring for dermatologic purposes.71 The recent trend for pulse IV CS therapy is administration in an ambulatory setting if there is no significant renal or cardiac disease present. The suppression of various lymphocyte subsets is greater with pulse CS therapy than with standard doses of oral CS therapy.72 CS-induced apoptosis likely plays a key role in this greater effect of IV pulse CS therapy. In addition, there appears to be a persistent decrease in natural killer cell activity. Other immunologic effects are qualitatively similar to those of oral administration. Summary. The overall interest in pulse CS therapy with IV methylprednisolone has waned over the recent decades. This modality should be used only when the severity of the patient’s condition and the lack of response to alternative modes of therapy indicate its appropriateness. Pulse IV methylprednisolone or dexamethasone therapy should be considered experimental and used very selectively in an individualized fashion.

Adverse Effects There is an imposing list of potential AE from the use of systemic CS (Box 13.5). Brief bursts of CS for 2 to 3 weeks are surprisingly safe and very useful in self-limiting dermatoses (Box 13.6). Q13.6 Lower-dose long-term regimens at or very near replacement (physiologic) levels of CS also are reasonably safe. Disease control and HPA-axis suppression are two key issues that determine the rapidity of systemic CS dose tapering, and HPA-axis suppression with the risk of CS withdrawal syndrome is primarily an issue when dosing below ‘physiologic’ dose levels. With supraphysiologic (pharmacologic) doses longer than 3 to 4 weeks there is an increased risk for more serious complications. The most serious AE come from relatively long-term use at doses well above replacement (physiologic) levels. Patients with bullous dermatoses, autoimmune connective tissue diseases, vasculitis, and neutrophilic dermatoses all frequently need such longer-term pharmacologic-level doses of CS. Cutaneous AE and their proposed underlying mechanisms are listed in Table 13.6. General Points Regarding Tables for Adverse Effects.

Q13.7 Risk factors for CS AE and measures for prevention, recognition, and management of important AE (Table 13.7) are essential to understand, in order to maximize the safety of prescribing systemic CS. The tables are not intended to be comprehensive; instead, the focus is on central issues relating to the most important CS AE from the standpoint of magnitude of risk and frequency of occurrence. The reviews footnoted as a basis for these tables can provide further background information and detailed references for interested readers.

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• BOX 13.5 Important Adverse Effects of Systemic Corticosteroids by Category72–75,119 Hypothalamic-Pituitary-Adrenal Axis

Psychiatric

Steroid withdrawal syndrome Addisonian crisis

Psychosis Agitation or personality change Depression (Prednisone phobia or dependency)

Metabolic Glucocorticoid effects Hyperglycemia Increased appetite (and weight) Mineralocorticoid Effects (as a Result of Sodium Retention, Potassium Loss) Hypertension Congestive heart failure Excessive weight gain Hypokalemia Lipid Effects (↑ Lipolysis and Altered Fat Deposition) Hypertriglyceridemia Cushingoid changes

Neurologic Pseudotumor cerebri Epidural lipomatosis Peripheral neuropathy

Infectious Tuberculosis reactivation Opportunistic—deep fungi, others Prolonged herpes virus infections

Muscular Myopathy (with muscle atrophy)

Bone Osteoporosis Osteonecrosis Hypocalcemia (indirectly)

Pediatric Growth impairment

Cutaneous Gastrointestinal

See Table 13.6

Peptic ulcer disease Bowel perforation Fatty liver changes Esophageal reflux Nausea, vomiting

Pulse Therapy Electrolyte shifts Cardiac dysrhythmias Seizures

Ocular

Other

Cataracts Glaucoma Infections especially staphylococcal Refraction changes (from corticosteroid-induced hyperglycemia)

‘Opportunistic’ malignancies Teratogenicity—doubtful Menstrual irregularity

• BOX 13.6 Common Adverse Effects with Prednisone

Bursts—in Absence of Relative Contraindications Metabolic Increased appetite with weight gain Fluid retention with edema and possibly weight gain

Psychiatric Occasional patient may get ‘wired’ or ‘weird,’ especially if baseline characteristics Some patients may get depressed during tapering phase

Gastrointestinal Mild gastroenteritis symptoms

Potentially Fatal Complications. It is most unusual to have a fatal outcome when CS is prescribed for dermatologic indications. Drug-induced fatalities in older studies of CS (with or without other immunosuppressive agents) for pemphigus vulgaris are a noteworthy exception of historical significance. Q13.8 Table 13.8 provides relevant references for the AE of systemic CS that

have even a remote potential for a fatal outcome. A few points are highlighted for each of these AE below: • Adrenal crisis (Addisonian crisis)—In the current era this complication is extraordinarily rare. When in doubt, clinicians should err on the side of prescribing ‘stress CS doses’ when indicated.13,73–75 • Bowel perforation—Exercise tremendous caution with the use of systemic CS after recent bowel anastomosis and for patients with active diverticulitis.76,77 • Peptic ulcer perforation—This complication is most likely with adjunctive nonsteroidal anti-inflammatory drugs (NSAID) and patients with a history of peptic ulcer disease (PUD). Albeit controversial, proactive use of H2 antagonists or proton pump inhibitors for patients with prior history of PUD and for patients with symptoms even possibly related to PUD is suggested.78–80 • Pancreatitis—This complication largely occurs with an acute elevation of triglycerides greater than 800 mg/dL. The clinician should intervene promptly with any reports of severe abdominal pain with systemic CS use.81–84 • Severe hyperglycemia (diabetic ketoacidosis or hyperosmolar nonketotic coma)—Although occasionally this may occur de novo, most severe hyperglycemia occurs with pre-existing diabetes mellitus. The widespread availability of home glucose monitoring should make this a rare complication.85,86

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TABLE Cutaneous Adverse Effects From Systemic Corticosteroids13,63,119 13.6

Category

Mechanism

Adverse Effects

Wound healing and related changes

↓ Collagen, ground substance; ↓ Re-epithelialization, angiogenesis

Nonhealing wounds, ulcers, striae, atrophy, telangiectasias

Pilosebaceous

Pityrosporum ovale, androgenicity

‘Steroid acne,’ ‘steroid rosacea’

Vascular

Catabolic effects on vascular smooth muscle

Purpura, including actinic purpura

Cutaneous infections

See Table 7.3

Staphylococcal, herpes virus infections in particular

Hair effects

Uncertain for telogen effluvium

Telogen effluvium, hirsutism

Injectable CS

Lipolysis of subcutaneous fat

Fat atrophy; crystallization of injectable material

Other skin effects

↓ CS immunosuppression (taper) Insulin resistance

Pustular psoriasis flare, rebound of poison ivy/oak Acanthosis nigricans

CS, Corticosteroid.

• Opportunistic infections—These infections are distinctly uncommon with CS used for dermatologic indications, and occur primarily with multidrug immunosuppression regimens for systemic autoimmune disorders and for organ transplantation.87–92 The relative risk (RR) of tuberculosis is 7.7 (confidence interval [CI] 2.8–21.4) for prednisone doses of at least 15 mg daily, whereas at doses less than 15 mg daily the RR barely reaches significance (RR 2.8; CI 1.0–7.9). Immunosuppressive therapy (CS, other) significantly reduces purified protein derivative (PPD) screening reactivity. Although not ideal, interferon (IFN)-γ release assays (various names) are more reliable than a PPD in the presence of immunosuppressive therapy, including with CS therapy. Baseline screening for hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) should also be strongly considered. Additionally, prophylaxis for pneumocystis pneumonia and strongyloides infections can be considered in at-risk populations.93 • Immunosuppression carcinogenesis (‘Opportunistic malignancies’ denotes Kaposi sarcoma, non-Hodgkin lymphoma, squamous cell carcinoma, and Merkel cell carcinoma that are common in solid organ transplantation patients)—Likewise this complication is very uncommon with systemic CS for purely dermatologic indications.13,94 Pregnancy Risk. Several older studies have demonstrated increased teratogenesis in laboratory animals as a result of CS therapy. Cleft lip and palate are the most common specific malformations. Multiple studies in humans concerning patients with CS-dependent systemic conditions during pregnancy have demonstrated no significantly increased risk of congenital malformations in humans.95 In general, these studies have evaluated the use of CS for conditions in which there is a major maternal risk if systemic CS is withheld during pregnancy. These studies that documented no increased risk of teratogenicity include patients with systemic lupus erythematosus (SLE) and related autoimmune connective tissue diseases,96,97 severe asthma,98–100 and organ transplantation.101 As with any drug in pregnancy, CS should be used only when the drug is clearly indicated, and if the potential benefits far exceed the potential risk to the mother and fetus. Fetal HPA-axis suppression is important to consider, particularly when CS therapy is used near the time of delivery. There may be an increased risk of stillbirth and spontaneous abortion.72

Other Adverse Effects with the Potential for Serious Morbidity. Q13.7 A number of potentially serious complications

of systemic CS (as well as adrenal crisis and immunosuppression carcinogenesis, discussed earlier) have been reviewed.13 This monograph included thorough reviews of the following important potential CS complications: • Osteonecrosis (avascular necrosis, aseptic necrosis)—Brief bursts of systemic CS simply do not create a true risk for osteonecrosis. The medicolegal implications of this concept are very important. The vast majority of osteonecrosis cases in the literature are with pharmacologic doses of prednisone (or comparable doses of other systemic CS) for at least 2 to 3 months continuously for life-threatening conditions. There is no doubt that long-term (at least 3 months) continuous CS therapy increases the risk of osteonecrosis, with the greatest risk in SLE patients.13 The author (SEW) reviewed all studies with at least 100 patients on long-term CS for either SLE or renal transplantation; in a total of 39 studies, only two studies had even one patient develop osteonecrosis before 3 months of continuous CS therapy. Given the relative frequency of CS prescriptions (see earlier) and idiopathic osteonecrosis (≤30% of all cases), it is reasonable to speculate that the great majority (if not all) reports of osteonecrosis from CS bursts are because of chance overlap. • Osteoporosis—Preventive measures to retard the expected CSinduced bone calcium depletion for any patient receiving pharmacologic doses of CS for at least 1 month are imperative. The hierarchy of options includes calcium (1000–1500 mg daily), vitamin D (800 U daily), bisphosphonates, teriparatide, and nasal calcitonin. Bone density assessment with dual energy x-ray absorptiometry (‘DEXA’) scans has revolutionized the surveillance for this important complication. The great majority of CS AE are minimized by doses with chronic doses at or below physiologic range (5–7.5 mg of prednisone on a daily basis). In contrast, there is a significant risk of CS-induced osteoporotic fractures with prednisone doses between 2.5 and 5 mg daily; therefore, clinicians should be proactive with pharmacologic measures to prevent osteoporosis (calcium, vitamin D, and ideally bisphosphonates) even in this dose range. CS therapy has been ‘attributed’ to induce 47% of all hip fractures and 72% of all vertebral fractures.

TABLE Overview of Selected Corticosteroid Adverse Effects13,19,20,63,93,102,120–122 13.7

Adverse Effect

Proposed Mechanisms

CS Therapy Factors

Additional Risk Factors

Preventiona

Diagnosis

Management

HPA-Axis Effects Adrenal crisis

Reduced GC and MC reserves—normally there are adequate compensatory mechanisms for GC and MC effects such that major complications are very rare in dermatologic therapy

Abrupt cessation of CS (in addition to major stressors) in patients on >20 mg daily for >3 weeks

Major surgery, trauma, or illness; severe gastroenteritis with fluid and electrolyte loss

‘Stress dose’ CS (see text)

History (see text)

Fluids and glucocorticoid replacement

CS withdrawal syndrome

Reduced GC and MC

Abrupt CS tapering with intermediate and chronic duration therapy

None

Appropriate CS tapering

History (see text)

Raise CS dose, then taper much more slowly

Hyperglycemia

GC effects—↑ hepatic glucose/glycogen production, ↑ gluconeogenesis via protein catabolism, induce insulin resistance producing ↓ glucose entry into cells

Especially with high CS dose

Family or personal history of DM, obesity; rarely de novo DM development (is generally reversible); traditional risk factors are less often present in medicationinduced diabetes

Dietary measures, recommend glucometer

Fasting glucose levels

ADA diet, insulin, OHGA, insulin sensitizers, etc.

Hypertension

MC effects—sodium retention; also in part due to GC-induced vasoconstriction

CS with high MC effect, therapy over 1 year, pulse CS

Prior hypertension, elderly patients; rarely occurs with bursts of CS

Sodium restriction, choose CS with low MC effect

Monitor blood pressure; usually mild elevation

Initially sodium restriction, thiazide diuretic

Congestive heart failure

MC effects—↑ sodium retention, resultant fluid overload in predisposed individuals

CS with high MC effect

Prior well- or partially compensated CHF

Sodium restriction, choose CS with low MC effect

History, examination, weights

Initially sodium restriction, thiazide diuretic

Hyperlipidemia

GC effects—overall result of catabolic state, in part initiated by ↑ lipoprotein lipase

Especially with high CS dose

Caloric/saturated fat excesses, personal or family history of hyperlipidemia, DM, hypothyroidism

Low-calorie, lowsaturated fat diet

Triglyceridesb (milder cholesterol elevations)

Gemfibrozil, ‘statins’

Metabolic Effects

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Continued

146

TABLE Overview of Selected Corticosteroid Adverse Effects13,19,20,63,93,102,120–122—cont’d 13.7

Proposed Mechanisms

Cushingoid changes

Additional Risk Factors

Preventiona

Diagnosis

Management

Altered fat distribution, uncertain mechanism; result of overall fat catabolism

CS for at least 2–3 months

Excessive caloric intake because of increased appetite

Dietary measures, exercise

Examination, weights

Low-calorie diet, exercise

Growth impairment

As a result of ↓ growth hormone and IGF-1 production; net result delayed skeletal maturation

Chronic pharmacologic dose CS therapy, ↓↓ with QOD

Transplantation or autoimmune condition in children requiring indefinite CS therapy

Low single AM dose of CS; QOD also helpful

Plotting height and weight on growth chart in children

If possible taper CS; possibly growth hormone

Osteoporosisc

↑ Osteoclast activity, ↓ osteoblast activity, ↓ GI absorption of calcium, ↑ renal excretion of calcium; resultant secondary hyperparathyroidism and bone resorption

No decrease with QOD CS

Female gender, increased age, thin, inactive patients, previous fracture, smoking, alcohol use, history of falls, vitamin D deficiency at highest risk; men at risk as well (overall highest risk of bone loss in young men)

Calcium 1200 mg and vitamin D 800 IU, physical activity

Serial bone densitometry (annually or based on risk), abnormal T score 65 years, smoking, alcohol, history of PUD, Helicobacter pylori or autoimmune connective tissue disease

H2 antihistamines in higher-risk patients

History; upper GI endoscopy

H2 antihistamines, proton pump inhibitors

Bone Effects

Gi Effects

Systemic Immunomodulatory Drugs

CS Therapy Factors

PART IV

Adverse Effect

TABLE Overview of Selected Corticosteroid Adverse Effects13,19,20,63,93,102,120–122—cont’d 13.7

Adverse Effect

Proposed Mechanisms

CS Therapy Factors

Additional Risk Factors

Preventiona

Diagnosis

Management

Other Adverse Effects No decrease with QOD CS

Baseline lens opacities, older patients, children

Sunglasses may help

Slit-lamp examination every 6–12 months

If advanced, cataract removal and lens implant

Agitation/ psychosis

Possibly because of electrolyte shifts, altered nerve excitability, possibly mild cerebral edema

CS at least 40 mg/ day; doses above 80 mg/day high risk

Family history of psychosis, baseline high anxiety, female gender (especially day 15–30 of CS course)

Careful patient selection if prior psychiatric disorder

History; depression may occur during tapering

Doxepin (if agitation); may need lithium (found effective for prophylaxis and management) or antipsychotics12,7

Opportunistic infections

Impaired immunologic responses—see Table 13.2

Prolonged high CS dose; ↓↓ risk with QOD. CS

Multidrug immunosuppression therapy, transplantation patients with ‘foreign’ antigen present long-term. High-risk dermatology population includes patients with SLE, dermatomyositis, or immunobullous disease on another immunosuppressive agent or who have a history of hematologic malignancy or interstitial lung disease

Pretreatment testing (HIV, hepatitis B, hepatitis C, TB) and vaccinations including VZV in patients age >50–60 years); Pneumocystis pneumonia prophylaxis with TMP-SMX DS 160/800 mg TIW or dapsone 100 mg daily

High index of suspicion (may not manifest symptoms of infection as clearly as immunocompetent patients); consider strongyloides screening with IgG antibodies in patients with peripheral eosinophilia in endemic areas

Varies

Myopathy

↓ Glucose and amino acid uptake by muscles, leading to muscle atrophy/ wasting

Fluorinated CS, rapid CS taper

Lack of exercise

Exercise, caution with CS tapering after high-dose therapy

Proximal muscle weakness, may have pain; muscle enzymes often normal

Gradual taper of CS dose; exercise especially if muscle atrophy/wasting

aIn

each of the above adverse effects, careful dosing is important for prevention; anticipate high-risk patients. caution should be exercised with triglyceride levels over 400–500 mg/dL; risk of pancreatitis becomes significant with levels above 800 mg/dL. cGreatest CS effect on bone resorption at sites of high trabecular bone content such as ribs, vertebral bodies and flat bones of pelvis—correspond to sites with greatest risk of fractures. ADA, American Diabetes Association; CHF, congestive heart failure; CS, corticosteroid; DM, diabetes mellitus; GC, glucocorticoid; GI, gastrointestinal; HPA, hypothalamic-pituitary-adrenal; IGF-1, insulin-like growth factor 1; IgG, immunoglobulin G; MC, mineralocorticoid; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-inflammatory drug; OHGA, oral hypoglycemic agent; TB, tuberculosis; TMP-SMX DS, trimethoprim-sulfamethoxazole double strengthL; VZV, varicella zoster virus. bParticular

Systemic Corticosteroids

Altered lens proteins, with uncertain mechanism (typically posterior subcapsular)

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TABLE Corticosteroid Complications That May Rarely Be Fatal 13.8

Complication Adrenal

crisis8,64,102

Comments Distinctly uncommon currently perhaps because of heightened awareness, aggressive emergency room, or postoperative preventive and therapeutic measures

Bowel perforation76–78

Best treatment is prevention; can have catastrophic outcome if late diagnosis

Perforated PUD79,80

Typically factors such as ASA or NSAID, known history of PUD present, heavy tobacco or alcohol use, patients >65 years of age, and patients taking other medications that increase risk such as bisphosphonates; gastric ulcers and perforation more common than duodenal

Pancreatitis81–84

Primarily a result of triglyceride elevations >800 mg/dL, typically occurs in the first 2–4 weeks of therapy; possible role of increased viscosity of pancreatic secretions leading to obstruction

Severe hyperglycemia85,86

Risk primarily if diabetic ketoacidosis or hyperosmolar nonketotic coma results; overall these complications are rare, perhaps due in part to home glucose monitoring

Opportunistic infectionsa 87–93

Strikingly uncommon in dermatologic therapy, at-risk groups include patients with systemic lupus erythematosus, dermatomyositis, or immunobullous disease on ≥1 additional immunosuppressive agent in addition to CS and have other serious comorbidities including malignancy or interstitial lung disease; greater risk with multidrug immunosuppressive regimens common with organ transplantation

‘Opportunistic’ malignanciesb 13,94

Primarily with CS in multidrug immunosuppression regimens in transplantation settings; Kaposi sarcoma may be an exception with CS use alone

aOpportunistic infections occasionally present in patients receiving CS for inflammatory or autoimmune conditions include infections caused by candidiasis (unusual locations), cryptococcosis, aspergillosis,

listeriosis, herpes virus (widespread), cytomegalovirus, Pneumocystis jiroveckii, and strongyloidiasis. in this case refers to predominantly viral-induced malignancies, which are markedly increased with multidrug immunosuppression regimens most commonly used in transplantation setting—especially non-Hodgkin lymphomas, Kaposi sarcoma, Merkel cell carcinoma, and cutaneous/female genitourinary tract squamous cell carcinomas. ASA, Aspirin; CS, corticosteroid; NSAID, nonsteroidal anti-inflammatory drug; PUD, peptic ulcer disease.

b’Opportunistic’

• Growth impairment in children—This is rarely an issue for dermatologic indications. Even with CS use in transplantation settings and for serious systemic autoimmune conditions in children, catch-up growth is possible when CS are reduced to physiologic levels or below. Attempt to wean CS as soon as possible in pediatric patients and consider referral to a pediatric endocrinologist for any patient who requires ongoing or repeated doses of CS for disease management. Miscellaneous Noteworthy Adverse Effects.

• Lipodystrophy and related metabolic syndrome changes— Up to 66% of patients on long-term therapy of at least 20 mg of prednisone daily have lipodystrophy, including moon face, ‘buffalo hump,’ and central obesity. The lipodystrophy is associated with increased risk of metabolic syndrome (increased body mass index, hypertension, hyperlipidemia, hyperglycemia), with resultant increased cardiovascular disease risk. This abnormality is the most distressing aspect of CS therapy to patients, possibly affecting compliance. Prednisone doses > itraconazole > fluconazole (only ≥300 mg daily)

same

Hormonal contraceptives

Various

CYP3A4 substrates; can ↑ CS half-life, ↓ clearance with resultant ↑ CS levels

Rifamycin antibacterials

Rifampin, rifabutin, rifapentine

CYP3A4 induction with resultant ↓ CS drug levels and loss efficacy; this effect takes 1–2 weeks; especially with dexamethasone, methylprednisolone

Aromatic anticonvulsants

Phenytoin, carbamazepine, oxcarbazepine, phenobarbital

same

Antifungals

Griseofulvin

same

Antituberculous

Isoniazid

Unknown mechanism ↓ CS drug levels

Vitamin D3

Calcitriol

May ↓ calcitriol therapeutic effect; unknown mechanism

Bile acid sequestrants

Cholestyramine

May ↓ CS absorption with loss of efficacy; give CS 2 hours before or 6 hours after cholestyramine

Relatively High-Risk Drug

Interactionsa

Lower-Risk Drug Interactions

CS, Corticosteroid; CYP, cytochrome P-450; DM, diabetes mellitus; GI, gastrointestinal; HBP, high blood pressure; JAK, janus kinase; NSAID, nonsteroidal anti-inflammatory drug; OHGA, oral hypoglycemic agent; PUD, peptic ulcer disease; SAE, serious adverse event. aOverall highest-risk drug interactions indicated in bold italics. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. (http://www.hanstenandhorn.com/).

tends to produce greater HPA-axis suppression. One study evaluated a 4-hour delayed-release version of prednisone that, when taken at 10:00 PM and released at 2:00 AM, can better suppress the IL-6 (and other cytokines) that produce morning stiffness. It is possible that similar dermatologic applications of this delayedrelease prednisone are forthcoming. Corticosteroid Dosing Principles for Children. Chronic systemic CS therapy for dermatologic conditions are uncommonly required in pediatric patients.113,114 Conditions such as severe Rhus dermatitis will occasionally require a 2 to 3-week burst of CS. Typically, 1 mg/kg daily is initially given; the dose is halved every 4 to 7 days. This approach has no significant sustained effect on growth and is safe for the pediatric patient who has no significant relative contraindications.

Corticosteroid Formulation Choice. Prednisone is generally the systemic CS of choice for most dermatoses. Prednisone is inexpensive and comes in multiple dosage options, which allows easy titration of the dose to obtain maximal therapeutic efficacy and safety. The prednisone dosage ranges are reasonably well standardized for most conditions treated. In addition, the prednisone duration of action is optimal for allowing daily or alternate-day therapy. In Europe, prednisolone is commonly used instead of prednisone. Prednisolone (1) requires no metabolic conversion to be active, (2) has a quicker onset of action, and (3) has a CBG affinity greater than that of prednisone. Drawbacks to routine prednisolone use include its greater cost and smaller number of dosage options (only 5-mg tablets, plus liquid formulations of 5 mg/5 mL and 15 mg/5 mL available).

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• BOX 13.7 Corticosteroid Monitoring Guidelines13,93,102,117,120–122 Baseline (When Anticipating Long-term Corticosteroid Therapy) History • Obtain vaccination history [hemophilus influenza B, hepatitis A, hepatitis B, human papillomavirus, influenza, neisseria meningitides, rubella (for women of childbearing age), streptococcus pneumoniae, tetanus toxoid, varicella zoster]

• Consider pneumocystis pneumonia prophylaxis if appropriate

Follow-up (With Long-term CS Therapy above Physiologic Dose Levels) Examination

• Blood pressure, weight • Height and weight plotted on a growth curve (in children) • Ophthalmoscopic examination for cataracts

At 1 month, then at least every 2–3 months: • Blood pressure, weight • Height and weight plotted on a growth curve (in children) • Thorough history each visit for adverse effectsa At least every 6 months initially; at least every 12 months long term: • Ophthalmologic examination for cataracts and glaucoma

Laboratory

Laboratory

Examination

• Tuberculosis screening—interferon-γ-releasing assay > tuberculin skin test, chest x-ray • Strongly consider screening for hepatitis B, hepatitis C, human immunodeficiency virus • Consider screening for Strongyloides in endemic areas (rural Appalachia, immigrants) • Fasting glucose or hemoglobin A1c and triglycerides; potassium level • Baseline bone densitometry

At 1 month, then at least every 3–4 months while on pharmacologic dose CS: • Potassium levels • Glucose levels (fasting) • Triglycerides (fasting) Near time of cessation of long-term pharmacologic dose CS therapy (optional): • AM cortisol level (or another suitable test of adrenal function or the entire HPA axis)

Additional Measures

Pulse Intravenous Methylprednisolone Therapy

• Initiate calcium 1200 mg and vitamin D 800 IU daily; consider bisphosphonate if appropriate (alendronate or risedronate recommended) • Initiate proton pump inhibitor if indicated for gastrointestinal prophylaxis • Discuss vaccination with primary care in accordance with standard scheduling

• Cardiac monitoring (see text discussion) • Daily electrolyte and glucose levels

TABLE Corticosteroid Adverse Effects for Which Home 13.13 Monitoring by the Patient is Possible

Adverse Effect

Home Monitoring Measure

Hyperglycemia

Home glucose monitoring devices

Hypertension

Home blood pressure cuffs/electronic devices

Fluid overload

Weighing self on bathroom scale

Weight gain

Weighing self on bathroom scale

Overall, the MC effect and duration of action are much more important factors in the choice of CS therapy than is the antiinflammatory potency of the product. Various preparations have equivalent anti-inflammatory efficacy at therapeutically equivalent doses. As per Table 13.1, (1) cortisol and cortisone have the greatest MC activity, (2) dexamethasone, betamethasone, and methylprednisolone have the least MC activity, and (3) prednisolone, prednisone, and triamcinolone have intermediate MC activity. Prednisone and prednisolone share a reasonable profile of MC effect and duration of action compared with other short-acting alternatives. Lower-potency short-acting CS such as hydrocortisone may not allow for steady day-long control of the disease activity. The MC effect of hydrocortisone is excessive, should the potential for sodium and fluid retention be deleterious to a specific patient. Hypertension from CS appears to be largely independent of their natriuretic effect, and is probably more related to vasoconstriction and increase myocardial contractility. The long-acting CS betamethasone and dexamethasone produce a much greater risk of HPA-axis suppression than intermediate-acting CS (prednisone,

More frequent surveillance is needed if laboratory values are abnormal or with high-risk patients.

• BOX 13.8 Important Principles to Maximize the

Safety of Systemic Corticosteroids in General (See Also Chapter 2) First and foremost, prescribe systemic corticosteroid (CS) only for appropriate, well-documented indications Thoroughly understand (and use all possible measures to avoid) the most serious potential CS complications. Stress thorough patient education reinforced by a patient handout, striving to form a true therapeutic partnership. Match the aggression of CS therapy with risk of the disease being treated Find the lowest possible effective CS dose as soon as possible. Use a nonperfectionistic mindset for the completeness of disease control. Use attack (quickly control the disease process), then reasonably quickly retreat (taper CS) philosophy. Seek to attain physiologic or alternate-day doses within 1–2 months; if this is not possible (or unlikely to be possible) use ‘CS-sparing’ therapy. ‘CS-sparing’ therapy in a broad sense includes any topical or systemic adjunctive therapy which may allow a reduced oral CS dose. Proactively deal with precipitators for the disease being treated. In the presence of a relative contraindication for CS therapy, medical management of this ‘contraindication’ may allow careful CS therapy. Laboratory monitoring particularly for metabolic changes —potassium, glucose, triglycerides (likewise follow the blood pressure closely). In general, the proactive, careful clinician will: Anticipate (risk factors and relative contraindications) Prevent (be proactive regarding measures to prevent adverse effects) Diagnose early (monitor labs, home monitoring, patient awareness) Manage (should a significant adverse effect occur) potential adverse effects from CS therapy.

154

PA RT I V

Systemic Immunomodulatory Drugs

prednisolone, methylprednisolone). Therefore, if the patient has high blood pressure (and/or perhaps congestive heart failure), methylprednisolone (orally) provides the best ‘compromise’ of intermediate half-life (24–36 hours) and low MC effect. Tapering Principles. Tapering based on disease activity is performed to avoid undesirable flare-ups of a previously controlled dermatologic condition (Q13.11, Box 13.9, Table 13.14). Excessively rapid tapering will occasionally allow a marked rebound of disease activity, such as that seen at times with brief (1 month) would be to reduce the dose by 20% to 30% every 1 to 2 weeks as disease activity allows.

• BOX 13.9 Long-Term Corticosteroid Taper for

Pemphigus Vulgaris Prednisone >40 Mg/Day Taper by 10 mg/week to 40 mg daily Remain on 40 mg/day for 1 week

Prednisone 40 Mg/Day Taper by 5 mg/week to 20 mg daily Remain on 20 mg/day for 1 week

Prednisone 20 Mg/Day Taper by 2.5 mg/week to 5 mg daily Remain on 5 mg/day for 1 week

Prednisone 5 Mg/Day Taper by 1 mg/week until off prednisone Taper slowly to avoid both disease flare and adrenal insufficiency. This taper may be used for other dermatoses; clinicians must individualize taper based on disease activity and underlying comorbidities. More rapid tapering used for less serious dermatoses.

More serious conditions, such as pemphigus vulgaris, commonly require more gradual tapering at intervals of 3 to 4 weeks or more. An example regimen for long-term CS tapering for pemphigus vulgaris is outlined in Box 13.9. The prednisone dose should be increased to the last effective dose level if a significant disease flare occurs during the tapering process. When the daily dose exceeds physiologic levels for more than 1 month, clinicians should always consider attempting alternate-day therapy, discussed as follows. Nearing the end of long-term high-dose CS therapy, basal HPA function can be determined through a morning cortisol level. A cortisol value greater than 10 mg/dL ensures adequate basal HPA function, although stress doses of CS may still be appropriate as previously discussed. Most clinical scenarios in dermatology do not require this morning cortisol testing. Alternate-day Corticosteroid Therapy. The conceptual basis for alternate-day therapy is that the anti-inflammatory benefits of CS therapy persist longer than the duration of HPA-axis suppression when intermediate-duration CS therapy, such as prednisone, is used.4,115,116 During the ‘off day,’ cell-mediated immunity, white blood cells subset levels, and potassium excretion all are essentially normalized. Alternate-day CS therapy should be used to maintain disease activity suppression once adequate disease control has been obtained with daily CS therapy. Patients should be aware that complete suppression of disease activity on the ‘off day’ may not be possible. However, either small prednisone doses or other non-CS therapeutic measures can be used for minor symptoms during the off day. Q13.11 Various options for conversion from daily to alternate-day CS therapy are listed in Table 13.14. Q13.12 The risk of cataracts, osteoporosis, and possibly osteonecrosis are not reduced by alternate-day CS therapy of comparable doses. The HPA-axis recovery advantages of alternate-day therapy no longer exist once the dose reaches physiologic levels (10–15 mg of prednisone on alternate days). If tapering is proceeding quickly, it is reasonable to finish the tapering schedule with alternate-day doses. Otherwise, consider converting back to daily prednisone therapy at 5 mg daily (or less) and proceeding slowly with subsequent tapering. Some authors suggest conversion to the shorter-acting hydrocortisone at this point with unusually long courses of CS.

TABLE 13.14 General Principles for Successful Conversion to Alternate-Day Corticosteroid Therapy

Prerequisites Before Conversion to Alternate-Day Therapy Complete or nearly complete disease control has been attained Conversion to alternate-day therapy is most likely to succeed when prednisone dose is down to 20–30 mg daily (or less) Conversion only from daily AM doses (not from divided doses) Intermediate-duration CS such prednisone essential for alternate-day therapy to succeed

Options for conversion to alternate-day therapya

Examples in mg by daya

(1) Double the prior daily dose for the on day, and drop dose for the off day (if mild flare occurs or for more serious conditions, consider 2.5 times prior daily dose for on day dose)

(1) 20-20-40-0-40-0 (serious dermatoses consider 20-20-50-0)

(2) Gradually increase dose for on day, while decreasing by a similar amount for off day

(2) 20-20-25-15-30-10-35-5-40-0b

(3) Keep a constant dose for on day, while gradually decreasing dose for the off day

(3) 20-20-20-15-20-10-20-5-20-0b

aOnly options (1) and (2) keep the 2-day total CS dose at least at prior levels before initiating conversion to alternate-day therapy; in general this constant cumulative dose decreases the likelihood of a disease bFor

options (2) and (3) above, the clinician may continue each dosing level for two or more cycles, depending upon the severity of the disease treated. CS, Corticosteroid.

flare.

CHAPTER 13

Patient Involvement in the Therapeutic Process. Involvement of the patient and the patient’s family is important for long-term CS therapy. These individuals should be educated about important AE to report, follow-up visits required, and laboratory tests or special examinations necessary to monitor CS therapy. The patient (and family) should be informed about clinical scenarios that require stress doses of CS. Measures to reduce AE, such as calcium and vitamin D supplementation for prevention of osteoporosis, should be discussed early in CS therapy. Home monitoring of BP and glucose levels is important to consider in appropriate patients. MedicAlert bracelets or an identification card in the wallet should be carried to notify medical personnel of the patient’s long-term pharmacologic-dose CS therapy. Because of the numerous potential AE of CS therapy, the active participation of the patient and the patient’s family is of tremendous importance. Summary. Box 13.10 provides the reader with a concise summary of the ‘risk profile’ for systemic CS based on the ‘Drug Facts and Comparisons’ database.117

• BOX 13.10 Drug Risks Profile—Systemic

Systemic Corticosteroids

155

Bibliography: Important Reviews and Chapters Basic Science and Pharmacology Schimmer BP, Funder JW. Adrenocorticotropic hormone, adrenal steroids, and the adrenal cortex. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. New York: McGraw Hill; 2018:845–862. Sundahl N, Bridelance J, Libert C, De Bosscher KD, Beck IM. Selective glucocorticoid receptor modulation: new directions with non-steroidal scaffolds. Pharmacol Ther. 2015;152:28–41. Adverse Effects Overviews Caplan A, Fett N, Rosenbach M, Werth VP, Micheletti RG. Prevention and management of glucocorticoid-induced side effects: a comprehensive review (4 part series). J Am Acad Dermatol. 2017;76(1–2):1– 9. 11–16, 191–198, 201–207. Moghadam-Kia S, Werth VP. Prevention and treatment of systemic glucocorticoid side effects. Int J Dermatol. 2010;49(3):239–248. Rice JB, White AG, Scarpati LM, Wan G, Nelson WW. Long-term systemic corticosteroid exposure: a systematic literature review. Clin Ther. 2017;39(11):2216–2229. Wolverton SE. Major adverse effects from systemic drugs: defining the risks. Curr Probl Dermatol. 1995;7:1–40.

Corticosteroids Mechanisms of Action Buttgereit F, Straub RH, Wehling M, Burmester GR. Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action. Arthritis Rheum. 2004;50(11):3408–3417. Rhen T, Cidlowski JA. Anti-inflammatory mechanisms of glucocorticoids – new mechanisms for old drugs. N Engl J Med. 2005;353(16):1711–1721.

Contraindications Hypersensitivity to drug or components of formulation

Boxed Warnings None listed

Warnings & Precautionsa Hormonal aAdrenal suppression/hypothalamicpituitary-adrenal axis suppression (see text) aCaution with abrupt discontinuation of therapy Ocular aCaution with cataracts and/or glaucoma Musculoskeletal aMyopathy reported with high-dose corticosteroids (CS) aReduced bone mineral density with chronic CS Endocrine aDiabetes mellitus Changes in thyroid status may require dose adjustments Gastrointestinal aCaution with use in diverticulitis, peptic ulcer disease, inflammatory bowel disease—risk perforation

Immunosuppression incidence of secondary infections Mask acute infections (including fungal infections) Prolong or exacerbate viral infections Limit response to vaccines aAvoid use with ocular herpes aAvoid use with latent or active tuberculosis Cardiovascular aHypertension aCongestive heart failure, fluid overload Psychiatric aDepression (esp. with tapering) Psychosis (esp. with high-dose CS), personality changes aEuphoria, insomnia aIncreased

Pregnancy Prescribing Status Traditional US Food and Drug Administration (FDA) —category C (Budesonide category B) aUnder ‘Warnings

Newer rating b—Moderatehigh risk

& Precautions’ these adverse effects can be considered relatively high risk or important clinical scenarios to avoid. bSee Chapter 65 Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for ‘Newer rating’ based on 2015 FDA rulings. Data from Facts & Comparisons eAnswers (online database) accessed in 2018. St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/).

Intramuscular Corticosteroids Thomas LW, Elsensohn A, Bergheim T, Shiu J, Ganesan A, Secrest A. Intramuscular steroids in the treatment of dermatologic disease: a systematic review. J Drugs Dermatol. 2018;17(3):323–329.

References* 5. Schimmer BP, Funder JW. Adrenocorticotropic hormone, adrenal steroids, and the adrenal cortex. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. New York: McGraw Hill; 2018:845–862. 10. Rhen T, Cidlowski JA. Antiinflammatory mechanisms of glucocorticoids – new mechanisms for old drugs. N Engl J Med. 2005;353(16):1711–1721. 11. Buttgereit F, Straub RH, Wehling M, Burmester GR. Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action. Arthritis Rheum. 2004;50(11):3408–3417. 13. Wolverton SE. Major adverse effects from systemic drugs: defining the risks. Curr Probl Dermatol. 1995;7:1–40. 55. Yu SH, Drucker AM, Lebwohl M, Silverberg JI. A systematic review of the safety and efficacy of systemic corticosteroids in atopic dermatitis. J Am Acad Dermatol. 2018;78(4):733–740. 59. Han Y, Zhang J, Chen N, He L, Zhou M, Zhu C. Corticosteroids for preventing postherpetic neuralgia. Cochrane Database Syst Rev. 2013;3:CD005582. 112. Marik PE, Varon J. Requirement of perioperative stress doses of corticosteroids: a systematic review of the literature. Arch Surg. 2008;143(12):1222–1226. 118. Thomas LW, Elsensohn A, Bergheim T, Shiu J, Ganesan A, Secrest. Intramuscular steroids in the treatment of dermatologic disease: a systematic review. J Drugs Dermatol. 2018;17(3):323–329. 119. Rice JB, White AG, Scarpati LM, Wan G, Nelson WW. Long-term systemic corticosteroid exposure: a systematic literature review. Clin Ther. 2017;39(11):2216–2229. 122. Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9(1):30.

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86. Yang JY, Cui XL, He XJ. Non-ketotic hyperosmolar coma complicating steroid treatment in childhood nephrosis. Pediatr Nephrol. 1995;9:621–622. Infectious Complications 87. Wiest PM, Flanigan T, Salata RA, Shlaes DM, Katzman M, Lederman MM. Serious infectious complications of corticosteroid therapy for COPD. Chest. 1989;95:1180–1184. 88. Hellmann DB, Petri M, Whiting-O’Keefe Q. Fatal infections in systemic lupus erythematosus: the role of opportunistic organisms. Medicine. 1987;66:341–348. 89. Le Thi Huong D, Wechsler B, Piette JC, Bletry O, Godeau P. Pregnancy and its outcome in systemic lupus erythematosus. QJM. 1994;87:721–729. 90. Kraus A, Cabral AR, Sifuentes-Osornio J, Alarcón-Segovia D. Listeriosis in patients with connective tissue disease. J Rheumatol. 1994;21:635–638. 91. Katz A, Ehrenfeld M, Livneh A, et al. Aspergillosis in systemic lupus erythematosus. Semin Arthritis Rheum. 1996;26:635– 640. 92. Takeshita T. Bilateral herpes simplex virus keratitis in a patient with pemphigus vulgaris. Clin Exp Dermatol. 1996;21:291– 292. 93. Caplan A, Fett N, Rosenbach M, Werth VP, Micheletti RG. Prevention and management of glucocorticoid-induced side effects: a comprehensive review – infectious complications and vaccination recommendations. J Am Acad Dermatol. 2017;76:191–198. 94. Qian XC, Huang YZ, Huang RK. Kaposi’s sarcoma after steroid therapy for pemphigus foliaceus. Chin Med J. 1989;102:647– 649. Corticosteroids in Pregnancy 95. Fraser FC, Sajoo A. Teratogenic potential of corticosteroids in humans. Teratology. 1995;51:45–46. 96. Rayburn WF. Glucocorticoid therapy for rheumatic disease: maternal, fetal, and breast-feeding considerations. Am J Reprod Immunol. 1992;28:138–140. 97. Buchanan NM, Khamashta MA, Morton KE, Kerslake S, Baguley EA, Hughes GR. A study of 100 high-risk lupus pregnancies. Am J Reprod Immunol. 1992;28:192–194. 98. Stenius-Aarniala B, Piirila P, Teramo KA. Asthma and pregnancy: a prospective study of 198 pregnancies. Thorax. 1988;43:12–18. 99. Stenius-Aarniala B, Hedman J, Teramo KA. Acute asthma during pregnancy. Thorax. 1996;51:411–414. 100. Schatz M, Zeiger RS, Harden K, Hoffman CC, Chilingar L, Petitti D. The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol. 1997;100:301–306. 101. Wong KM, Bailey RR, Lynn KL, Robson RA, Abbott GD. Pregnancy in renal transplant recipients: the Christchurch experience. N Z Med J. 1995;108:190–192. Hypothalamic-Pituitary-Adrenal-Axis Suppression 102. Caplan A, Fett N, Rosenbach M, Werth VP, Micheletti RG. Prevention and management of glucocorticoid-induced side effects: a comprehensive review – gastrointestinal and endocrinologic side effects. J Am Acad Dermatol. 2017;76: 11–16. 103. Snow K, Jiang NS, Kao PC, Scheithauer BW. Biochemical evaluation of adrenal dysfunction: the laboratory perspective. Mayo Clin Proc. 1992;67:1055–1065. 104. Hasinski S. Assessment of adrenal glucocorticoid function. Which tests are appropriate for screening? Postgrad Med. 1998;104:61–64, 69–72. 105. Grinspoon SK, Biller BM. Clinical review 62; laboratory assessment adrenal insufficiency. J Clin Endocrinol Metab. 1994;79:923–931.

155.e3

106. Kahl L, Medsger Jr TA. Severe arthralgias after wide fluctuations in corticosteroid dosage. J Rheumatol. 1986;13:1063–1065. 107. Papanicolaou DA, Tsigos C, Oldfield EH, Chrousos GP. Acute glucocorticoid deficiency is associated with plasma elevations of interleukin-6; does the latter participate in the symptomatology of the steroid withdrawal syndrome and adrenal insufficiency? J Clin Endocrinol Metab. 1996;81:2303–2306. 108. Fabrega AJ, Corwin C, Martin M. Adrenal insufficiency [letter, comment]. N Engl J Med. 1997;336:1105–1107. 109. Levy A. Perioperative steroid cover [letter]. Lancet. 1996;347:846–847. 110. Friedman RJ, Schiff CF, Bromberg JS. Use of supplemental steroids in patients having orthopaedic operations. J Bone Joint Surg Am. 1995;77:1801–1806. 111. Salem M, Tainsh Jr RE, Bromberg J, Loriaux DL, Chernow B. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg. 1994;219:416–425. Therapeutic Guidelines 112. Marik PE, Varon J. Requirement of perioperative stress doses of corticosteroids: a systematic review of the literature. Arch Surg. 2008;143(12):1222–1226. 113. Lucky AW. Principles of the use of glucocorticosteroids in the growing child. Pediatr Dermatol. 1984;1:226–235. 114. Melo-Gomes JA. Problems related to systemic glucocorticoid therapy in children. J Rheumatol. 1993;20(suppl 37):35–39. 115. Fauci AS. Alternate-day corticosteroid therapy. Am J Med. 1978;64:729–731. 116. Dale DC, Fauci AS, Wolff SM. Alternate-day prednisone: leukocyte kinetics and susceptibility to infection. N Engl J Med. 1974;291:1154–1158. 117. Facts and Comparisons eAnswers. Prednisone. Facts & Comparisons [online database]. St. Louis, MO: Wolters Kluwer Health, Inc. https://www.wolterskluwercdi.com/facts-comparisons-online/. Accessed February 13, 2019. Tables 118. Thomas LW, Elsensohn A, Bergheim T, Shiu J, Ganesan A. Intramuscular steroids in the treatment of dermatologic disease: a systematic review. J Drugs Dermatol. 2018;17:323–329. 119. Rice JB, White AG, Scarpati LM, Wan G, Nelson WW. Longterm systemic corticosteroid exposure: a systematic literature review. Clin Ther. 2017;39:2216–2229. 120. Caplan A, Fett N, Rosenbach M, Werth VP, Micheletti RG. Prevention and management of glucocorticoid-induced side effects: a comprehensive review – a review of glucocorticoid pharmacology and bone health. J Am Acad Dermatol. 2017;76:1–9. 121. Caplan A, Fett N, Rosenbach M, Werth VP, Micheletti RG. Prevention and management of glucocorticoid-induced side effects: a comprehensive review – ocular, cardiovascular, muscular, and psychiatric side effects and issues unique to pediatric patients. J Am Acad Dermatol. 2017;76:201–207. 122. Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9:30. Dermatologic Uses Not Discussed in the Chapter Text Cicatricial Pemphigoid 123. Ahmed AR, Kurgis BS, Rogers 3rd RS. Cicatricial pemphigoid. J Am Acad Dermatol. 1991;24:987–1001. 124. Vincent SD, Lilly GE, Baker KA. Clinical, historic, and therapeutic features of cicatricial pemphigoid. A literature review and open therapeutic trial with corticosteroids. Oral Surg Oral Med Oral Pathol. 1993;76:453–459. 125. Sacher C, Hunzelmann N. Cicatricial pemphigoid (mucous membrane pemphigoid): current and emerging therapeutic approaches. Am J Clin Dermatol. 2005;6:93–103.

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Herpes Gestationis 126. Lawley TJ, Stingl G, Katz SI. Fetal and maternal risk factors in herpes gestationis. Arch Dermatol. 1978;114:552–555. 127. Morrison LH, Anhalt GJ. Herpes gestationis. J Autoimmun. 1991;4:37–45. Other Autoimmune Bullous Dermatoses 128. Callot-Mellot C, Bodemer C, Caux F, et al. Epidermolysis bullosa acquisita in childhood. Arch Dermatol. 1997;133:1122–1126. 129. Mobacken H, Kastrup W, Ljunghall K, et al. Linear IgA dermatosis: a study of ten adult patients. Acta Derm Venereol. 1983;63:123–128. 130. Jablonska S. The therapies for linear IgA bullous dermatosis of childhood. Pediatr Dermatol. 1999;16:415. Lupus Erythematosus 131. Lee LA, David KM. Cutaneous lupus erythematosus. Curr Probl Dermatol. 1989;1:165–200. 132. Callen JP, Klein J. Subacute cutaneous lupus erythematosus. Arthritis Rheum. 1988;31:1007–1013. 133. Fabbri P, Cardinali C, Giomi B, et  al. Cutaneous lupus erythematosus: diagnosis and management. Am J Clin Dermatol. 2003;4:449–465. Dermatomyositis 134. Krain LS. Dermatomyositis in six patients without initial muscle involvement. Arch Dermatol. 1975;111:241–245. 135. Callen JP. Dermatomyositis. Lancet. 2000;355:53–57. 136. Dawkins MA, Jorizzo JL, Walker FO, Albertson D, Sinal SH, Hinds A. Dermatomyositis: a dermatology-based case series. J Am Acad Dermatol. 1998;38:397–404. 137. Shehata R, al-Mayouf S, al-Dalaan A, al-Mazaid A, al-Balaa S, Bahabri S. Juvenile dermatomyositis: clinical profile and disease course in 25 patients. Clin Exp Rheumatol. 1999;17:115–118. 138. Choy EH, Isenberg DA. Treatment of dermatomyositis and polymyositis. Rheumatology. 2002;41:7–13. Vasculitis 139. Chua SH, Lim JT, Ang CB. Cutaneous vasculitis seen at a skin referral center in Singapore. Singapore Med J. 1999;40:147–150. 140. Lotti T, Ghersetich I, Comacchi C, Jorizzo JL. Cutaneous small-vessel vasculitis. J Am Acad Dermatol. 1998;39:667–690. 141. Callen JP, Ekanstam EA. Cutaneous leukocytoclastic vasculitis: clinical experience in 44 patients. South Med J. 1987;80:848–851. 142. Saulsbury FT. Henoch-Schonlein purpura in children. Report of 100 patients and review of the literature. Medicine. 1999;78:395–409. 143. Fauci AS. Wegener’s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med. 1983;98:76–85. 144. Guillevin L, Cohen P, Gayraud M, Lhote F, Jarrousse B, Casassus P. Churg-Strauss syndrome. Clinical study and long-term follow-up of 96 patients. Medicine. 1999;78:26–37. 145. Khoo BP, Ng SK. Cutaneous polyarteritis nodosa: a case report and literature review. Ann Acad Med Singapore. 1998;27:868–872. Pyoderma Gangrenosum 146. Johnson RB, Lazarus GS. Pulse therapy: therapeutic efficacy in the treatment of pyoderma gangrenosum. Arch Dermatol. 1982;118:76–84. 147. Prystowsky JH, Kahn SN, Lazarus GS. Present status of pyoderma gangrenosum. Review of 21 cases. Arch Dermatol. 1989;125:57–74.

148. Chow RK, Ho VC. Treatment of pyoderma gangrenosum. J Am Acad Dermatol. 1996;34:1047–1060. 149. Bennett ML, Jackson JM, Jorizzo JL, Fleischer Jr AB, White WL, Callen JP. Pyoderma gangrenosum. A comparison of typical and atypical forms with an emphasis on time of remission. Case review of 86 patients from 2 institutions. Medicine. 2000;79:37–46. 150. Wollina U. Clinical management of pyoderma gangrenosum. Am J Clin Dermatol. 2002;3:149–158. 151. Cairns BA, Herbst CA, Sartor BR, Briggaman RA, Koruda MJ. Periostomal pyoderma gangrenosum and inflammatory bowel disease. Arch Surg. 1994;129:769–772. 152. Graham JA, Hansen KK, Rabinowitz LG, Esterly NB. Pyoderma gangrenosum in infants and children. Pediatr Dermatol. 1994;11:10–17. Behçet Disease and Sweet Syndrome 153. Jorizzo JL. Behçet’s disease: an update based on the 1985 international conference in London. Arch Dermatol. 1986;122:556– 558. 154. Kaklamani VG, Vaiopoulos G, Kaklamanis PG. Behçet’s disease. Semin Arthritis Rheum. 1998;27:197–217. 155. MacPhail L. Topical and systemic therapy for recurrent aphthous stomatitis. Semin Cutan Med Surg. 1997;16:301–307. 156. Fett DL, Gibson LE, Su WP. Sweet’s syndrome: systemic signs and symptoms and associated disorders. Mayo Clin Proc. 1995;70:234–240. 157. von den Driesch P. Sweet’s syndrome (acute febrile neutrophilic dermatosis). J Am Acad Dermatol. 1994;31:535–556. Lichen Planus 158. Cribier B, Frances C, Chosidow O. Treatment of lichen planus. An evidence-based medicine analysis of efficacy. Arch Dermatol. 1998;134:1521–1530. 159. Lozada-Nur F, Miranda C. Oral lichen planus: topical and systemic therapy. Semin Cutan Med Surg. 1997;16:295–300. 160. Silverman Jr S, Bahl S. Oral lichen planus update: clinical characteristics, treatment responses, and malignant transformation. Am J Dent. 1997;10:259–263. 161. Thorn JJ, Holmstrup P, Rindum J, Pindborg JJ. Course of various clinical forms of oral lichen planus. A prospective study of 611 patients. J Oral Pathol. 1988;17:213–218. 162. Edwards L, Friedrich EG. Desquamative vaginitis: lichen planus in disguise. Obstet Gynecol. 1988;71:832–836. Sarcoidosis 163. Muthiah MM, Macfarlane JT. Current concepts in the management of sarcoidosis. Drugs. 1990;40:231–237. 164. Albertini JG, Tyler W, Miller 3rd OF. Ulcerative sarcoidosis. Case report and review of the literature. Arch Dermatol. 1997;133:215–219. 165. Milman N, Hoffman AL, Byg KE. Sarcoidosis in children. Epidemiology in Danes, clinical features, diagnosis, treatment and prognosis. Acta Paediatr. 1998;87:871–878. Other Dermatoses 166. Stone JJ, Elpern DJ. Sunburn. In: Provost TT, Farmer ER, eds. Current Therapy in Dermatology. 2nd ed. Toronto: Decker; 1988:164. 167. Negro-Alvarez JM, Carreño-Rojo A, Funes-Vera E, GarcíaCánovas A, Abellán-Alemán AF, Rubio del Barrio R. Pharmacologic therapy for urticaria. Allergol Immunopathol (Madr). 1997;25:36–51.

14 Methotrexate JEFFREY P. CALLEN AND CAROL L. KULP-SHORTEN

QUESTIONS Q14.1 What are the proposed mechanisms by which methotrexate inhibits inflammatory dermatoses? (Pg. 159x4)

Q14.8 Is there any definitive evidence that methotrexate increases the risk of lymphomas in psoriasis patients? (Pg. 165)

Q14.2 What is the biochemical rationale behind the use of (1) folinic acid, and/or (2) thymidine in patients with acute methotrexate liver toxicity (especially pancytopenia)? (Pg. 159)

Q14.9 Which drug interactions have the most serious potential with methotrexate therapy? (Pg. 165, Fig. 14.3, Table 14.1)

Q14.3 What are the pros and cons of routine folic acid supplementation with methotrexate therapy? (Pgs. 159, 163x2, 165) Q14.4 What are four to five dermatoses for which there is reasonable data concerning safety and efficacy regarding use of methotrexate in children? (Pg. 162, Box 14.1) Q14.5 What are the most important risk factors for methotrexateinduced liver disease? (Pg. 162) Q14.6 What are some of the noninvasive tests available to evaluate liver fibrosis with methotrexate therapy? (Pg. 163) Q14.7 Why is even a mild–moderate reduction in renal function important regarding the safe use of methotrexate? (Pg. 164)

Q14.10 What is the rationale for ultrasound-guided liver biopsies being the most appropriate method of obtaining tissue for liver histology? (Pg. 166, Table 14.2) Q14.11 What are the practical guidelines concerning which psoriasis patients should have a (1) true baseline liver biopsy, (2) a delayed baseline liver biopsy, and (3) an initial biopsy at 1.5 g cumulative dose? (Pg. 166x2) Q14.12 What are the pros and cons of the two common methods of administering weekly dosages of methotrexate, administered either as a single dose or in divided doses over 24 hours? (Pg. 167)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R ACR American College of Rheumatology AE Adverse effects (events) AICAR Aminoimidocarboxyamidoribonucleotide AIDS Acquired immunodeficiency syndrome AZA Azathioprine BP Bullous pemphigoid CBC Complete blood count DHFR Dihydrofolate reductase EBV Epstein-Barr virus FDA US Food and Drug Administration GI Gastrointestinal HIV Human immunodeficiency virus LPD Lymphoproliferative disorder MTX Methotrexate MI Myocardial infarction

NASH Nonalcoholic steatohepatitis NSAID(s) Nonsteroidal anti-inflammatory drug(s) PASI Psoriasis area and severity index PIIINP Aminoterminus type III procollagen peptide PLC Pityriasis lichenoides chronic PLEVA Pityriasis lichenoides et varioliformis acuta PRP Pityriasis rubra pilaris PUVA Psoralen and ultraviolet A RA Rheumatoid arthritis SCORAD Scoring Atopic Dermatitis TE Transient elastography (FibroscanTM) TMP-SMX Trimethoprim-sulfamethoxazole TNF Tumor necrosis factor WBC White blood cells

Introduction

(MTX, amethopterin), another folic acid antagonist, was also an excellent therapeutic agent for the control of psoriasis. Despite this discovery, it took nearly 20 years for the US Food and Drug Administration (FDA) to approve MTX for use in psoriasis.2 Only in the late 1980s was rheumatoid arthritis (RA) approved as

In 1951, Gubner and colleagues recognized that the folic acid antagonist aminopterin was effective for the treatment of psoriasis.1 Shortly after this observation, it was recognized that methotrexate 156

Methotrexate

CHAPTER 14

157

Monoheptaglutamate

Pteroyl

OH O

N CH2

N

H N

NH

OH N H

H O

N

N

H2N

O

Folic acid N

H2N

N CH3

N

N

N

O NH2

H N

OH OH

H O Methotrexate

• Fig. 14.1

O

Methotrexate and folic acid.

another indication for the use of MTX.3 Despite large numbers of patients who have been treated with MTX, there remain many areas of controversy and confusion regarding the indications for, and the safety of this chemotherapeutic and immunosuppressive agent. Included among these controversies are: (1) the criteria for selection of the psoriatic patient to receive MTX, (2) the method of laboratory evaluation, and (3) the need for liver biopsies and/ or noninvasive tests in surveillance. With the approval of multiple new agents for the treatment of psoriasis, the use of MTX has declined; however, concomitant use of MTX with the tumor necrosis factor (TNF)-α antagonists is approved for patients with psoriatic arthritis and RA, and we predict that this use in psoriasis will increase in the future despite its not being an FDA-approved indication. In this chapter, the existing scientific information on the pharmacology of, the indications for, and the adverse effects (AE) of MTX are reviewed.

Pharmacology Structure MTX (4-amino-N10methyl pteroylglutamic acid) is a potent competitive antagonist (inhibitor) of the enzyme dihydrofolate reductase (DHFR). It is structurally similar to folic acid, the natural substrate for this enzyme, differing from folic acid in only two molecular sites. The amino group in the 4-carbon position takes the place of a hydroxyl group, and a methyl group at the N10 position substitutes for the hydrogen atom (Fig. 14.1).

Absorption and Distribution MTX can be administered orally, intravenously, intramuscularly, or subcutaneously. It is rapidly absorbed through the gastrointestinal (GI) tract, although peak levels occur more slowly (1 hour after ingestion) through this route than through the other two routes of administration. Although absorption of oral MTX may be incomplete and variable with doses greater than 15 mg4 this

route of administration provides more reliable blood levels than parenteral administration.5 Concurrent food intake, especially milk-based meals, may reduce bioavailability in children.6 However, in adults, the drug is unaffected by concurrent food ingestion.7 In addition, nonabsorbable antibiotics, such as neomycin may reduce the absorption of MTX significantly. The drug is well distributed throughout the body except in the brain, penetrating the blood-brain barrier poorly (thereby explaining why intrathecal MTX is needed in some chemotherapy regimens).

Metabolism and Excretion Once absorbed, the level of MTX in the plasma has a triphasic reduction. The first phase occurs rapidly (0.75 hours) and reflects distribution of the drug throughout the body. The second phase of the plasma level reduction is represented by renal excretion and occurs over 2 to 4 hours. MTX is a weak organic acid excreted predominantly through the kidneys. Therefore glomerular filtration and active tubular secretion are susceptible to drug interactions with other weak acids, such as salicylates, probenecid, and sulfonamides. The third phase represents the terminal half-life and varies between 10 and 27 hours. This phase is thought to reflect a slow release of MTX, primarily bound to DHFR, from the tissues. Approximately 50% of MTX is bound to plasma proteins, and the active portion of the drug is the free fraction (unbound) in the plasma. Thus, any drug that may increase the unbound MTX portion (such as sulfonamides and salicylates; see Table 14.1 for others) may increase the beneficial tissue effects, as well as increasing the potential for toxicity. MTX is actively transported into cells, rather than entering by diffusion. It was previously thought that MTX is not substantially metabolized; however, evidence suggests that the drug is metabolized intracellularly, including by the liver, to polyglutamated forms.8,9 These metabolites, also potent inhibitors of DHFR, are long-lived active compounds and are postulated to play a key role in MTX toxicity. Intracellular MTX polyglutamates have been proposed as potential biomarkers of MTX efficacy and toxicity in the treatment of inflammatory

158

PA RT I V

Systemic Immunomodulatory Drugs

TABLE Drug Interactions—Methotrexate 14.1

Drug Category Relatively High-Risk Drug

Drug Examples

Comments

Interactionsa

Folate antagonists

DHPS—sulfamethoxazole, dapsone

Sulfonamides, dapsone inhibit first enzyme in two-step folate reduction pathway → myelosuppression

Folate antagonists

DHFR—trimethoprim

Methotrexate (MTX), trimethoprim inhibit second enzyme in folate reduction → myelosuppression

Habits

Alcohol

Much of chronic liver disease from MTX with accompanying chronic alcohol intake

Immunosuppressants

Wide variety—relatively uncommon to have these SAE in dermatology

Biologics, JAK inhibitors, traditional (azathioprine, cyclosporine, mycophenolates, etc.), chemotherapy, higher dose CS with risk of severe infections and/or myelosuppression

Vaccines—live attenuated

Zostavax and others

Vaccine efficacy may be reduced; complete injection(s) at least 2 weeks before initiation immunosuppression

Retinoids

Acitretin

Concomitant long-term use of both drugs with possible outcome of chronic liver disease

Loop diuretics

Furosemide, ethacrynic acid, others

May ↑ MTX serum levels and potential ↑ toxicity

Antiplatelet drugs

Dipyrimadole

Intracellular accumulation of MTX and potential ↑ toxicity

Miscellaneous

Probenecid

same (in addition to competing with MTX for renal tubular secretion)

Aromatic anticonvulsants

Phenytoin

Displacement of MTX from plasma proteins with ↑ MTX levels and associated toxicity; in reality the effect is transient and lower risk than originally thought

Tetracycline antibacterials

Doxycycline, minocycline

same

Anti-inflammatory

Aspirin, NSAID

same

Antipsychotics

Phenothiazines

same

Vaccines—inactivated or recombinant

Shingrix and many others

Vaccine efficacy may be reduced; complete injection(s) at least 2 weeks before initiation immunosuppression

Bile acid sequestrants

Cholestyramine

May ↓ MTX absorption with loss of efficacy; give MTX 2 hours before or 6 hours after cholestyramine

Lower-Risk Drug Interactions

aOverall highest-risk drug interactions indicated in bold italics. The dramatic increase in number of drug interactions in medicine requires some degree of selectivity in these tables (common usage, relative risk, focus on outpatient rx) CS, Corticosteroids; DHFR, dihydrofolate reductase; DHPS, dihydropteroate synthetase; JAK, janus kinase; NSAID, nonsteroidal anti-inflammatory drugs; SAE, serious adverse effect(s).

Data from Facts & Comparisons eAnswers [online database]. St. Louis: Wolters Kluwer. [https://www.wolterskluwercdi.com/facts-comparisons-online/]; Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. [http://www.hanstenandhorn.com/].

Methotrexate Partially reversible X inhibition

Irreversible inhibition X

Folic acid

• Fig. 14.2

Dihydrofolate reductase

Tetrahydrofolate

Thymidylate synthetase

DNA

Methotrexate and folate metabolism. DNA, Deoxyribonucleic acid.

CHAPTER 14

Methotrexate

159

F Folate (Folic acid)

Folinic acid G (Leucovorin)

D Dapsone Sulfonamides

A Dihydropteroate synthetase

Dihydrofolate C B

Methotrexate Trimethoprim

Dihydrofolate reductase E Tetrahydrofolate

* In general, this metabolic pathway is more important to the adverse effects of methotrexate (including drug interactions) than it is for drug efficacy. The fully reduced tetrahydrofolate is important for subsequent pyrimidine nucleotide synthesis. A Folate (folic acid) is initially reduced to dihydrofolate by dihydropteroate synthetase. B Dihydrofolate is further reduced to tetrahydrofolate by dihydrofolate reductase. C Methotrexate inhibits this pathway through competitive inhibition of dihydrofolate reductase (DHFR). D Dapsone and various sulfonamides inhibit dihydropteroate synthetase, and thus, can amplify the inhibition of DHFR by methotrexate. E Trimethoprim (including fixed combinations with sulfamethoxazole) also inhibits DHFR, and thus can amplify the inhibition of this pathway by methotrexate. F Folic acid given in therapeutic doses essentially competes with methotrexate for DHFR, the adverse effects of methotrexate by tetrahydrofolate production. G Folinic acid, in a sense does an “end run” around the methotrexate inhibition of folate, serving as a fully reduced substrate for pyrimidine synthesis.

• Fig. 14.3

Methotrexate and folate metabolism, drug interactions of importance.

arthropathies.10 There is pharmacokinetic data in RA patients that switching from oral to parenteral administration results in an increase in long-chain polyglutamates; this correlates with a reduction in disease activity.11

Mechanism of Action Effects

on

Deoxyribonucleic

Acid

(DNA)

Synthesis.

Q14.1 MTX competitively and reversibly binds to DHFR within 1 hour, with an affinity greater than that of folic acid. This prevents the conversion of dihydrofolate to tetrahydrofolate. Tetrahydrofolate is a necessary cofactor in the production of 1-carbon units, which are critical for the synthesis of thymidylate and purine nucleotides needed for DNA and ribonucleic acid (RNA) synthesis. A less rapid, but partially reversible, competitive inhibition of thymidylate synthetase also occurs within 24 hours after administration of MTX (Fig. 14.2). Thus the overall effect of MTX is inhibition of cell division, being specific for the S phase (DNA synthesis) of the normal cell cycle. Q14.2 The inhibition of DHFR can be bypassed by leucovorin calcium (N5-formyl-tetrahydrofolate: folinic acid, citrovorum factor) or thymidine. Leucovorin, a fully reduced, functional folate coenzyme, bypasses the reaction catalyzed by DHFR. Thymidine, converted to thymidylate by thymidine kinase, bypasses the reaction catalyzed by thymidylate synthetase. Thus acute hematologic toxicity secondary to MTX can be reversed by high doses of folinic acid (leucovorin calcium) or thymidine. T-cell Effects. Q14.1 The mechanism of action of MTX in psoriasis was originally thought to be caused by the suppression of hyperproliferation of keratinocytes. However, Jeffes and colleagues12 demonstrated in an in vitro experiment that the effect of MTX on the proliferation of lymphoid cells is 1000 times greater than its effect on human keratinocytes. Thus at concentrations reached in vivo, it is most likely that MTX acts via an immunosuppressive mechanism, rather than as an antiproliferative agent

directed against the keratinocyte. Sigmundsdottir and colleagues have demonstrated depression of cutaneous lymphocyte-associated antigen-positive T cells and endothelial E-selectin in MTXtreated psoriatic patients. Therefore, not only does MTX affect the proliferation of lymphocytes, it also blocks migration of activated T cells into certain tissues.13 Immunosuppressive Effects. Q14.1 MTX has activity as an immunosuppressive agent. The effect probably occurs because of inhibition of DNA synthesis in immunologically competent cells. The drug can suppress primary and secondary antibody responses.14,15 There is no significant effect on delayed-type hypersensitivity. Anti-inflammatory Effects. Q14.1 It has been traditionally taught that both the beneficial effects and the toxicity of MTX were mediated through the inhibition of DHFR and subsequent inhibition of reduced folate necessary for DNA synthesis. There is reasonably strong evidence that the anti-inflammatory effects are predominantly mediated by adenosine. This increased adenosine production is the result of a complex interaction with aminoimidocarboxyamidoribonucleotide (AICAR) transformylase and ecto 5’ nucleotidase.16 Folic Acid Effects on Methotrexate Therapy. Q14.3 The use of folic acid as a method of inhibiting MTX-induced GI AE and reducing the risk of pancytopenia is controversial. Multiple studies, primarily in the rheumatology literature, have suggested that folic acid administration does not impair the efficacy of MTX (Fig. 14.3). Morgan and colleagues have confirmed these clinical observations and demonstrated that administration of folinic acid, but not folic acid, reduces the efficacy of MTX.17 However, Khanna and colleagues recently reported that the American College of Rheumatology responses for RA were lower when folic acid was used.18 Strober and Menon concluded in their review on this subject that patients with psoriasis did not lose efficacy when folic acid was used to limit toxicity.19 However, two controlled trials have demonstrated decreased efficacy of MTX with concomitant folic acid.20,21 A recent review of the literature by Al-Dabagh and

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• BOX 14.1 Methotrexate Indications US Food and Drug Administration-Approved Dermatologic Indications Psoriasis24–28 Sézary syndrome23,82

Off-label Dermatologic Uses Proliferative Dermatoses Pityriasis rubra pilaris30–32 Pityriasis lichenoides et varioliformis acuta33,79 Reiter disease34

Immunobullous Dermatoses Pemphigus vulgaris35,36,43 Bullous pemphigoid36–40,43 Cicatricial pemphigoid41 Epidermolysis bullosa acquisita42

Vasculitis—Neutrophilic Dermatoses Leukocytoclastic vasculitis61 Cutaneous polyarteritis nodosa62,63 Behçet disease63 Kawasaki disease64 Pyoderma gangrenosum65,66

Dermatitis Atopic dermatitis67,69

Other Dermatoses Autoimmune Connective Tissue Diseases Dermatomyositis44–48 Subacute cutaneous lupus erythematosus49–52 Systemic lupus erythematosus53 Systemic scleroderma54,60 Morphea/localized scleroderma55–58 Scleredema diabeticorum59

Sarcoidosis71–76 Keloids77 Lymphomatoid papulosis78 Keratoacanthomas (intralesional)80 Mycosis fungoides81,82 Cutaneous Crohn disease83,84 Chronic idiopathic urticaria87,88 Prurigo70 Alopecia areata85,86

• BOX 14.2 Drug Risks Profile—Methotrexate Contraindications Known hypersensitivity methotrexate or components of formulation Alcoholism, including alcoholic liver disease/chronic liver disease Pre-existing blood dyscrasias—severe ↓ Hgb, WBC, platelets

Boxed Warnings Should be prescribed on by clinicians experienced with drug Hepatotoxicity—hepatocellular liver injury, fibrosis/cirrhosis Pregnancy Opportunistic infections—pneumocystis jirovecii pneumonia Second malignancies—lymphomas (may regress after d/c MTX)

confirms a reduction in AE of MTX in psoriasis patients receiving concomitant folic acid. However, they also noted weaker evidence supporting a reduction in efficacy. Therefore, folic acid supplementation is not universal and is often only routinely recommended if laboratory abnormalities or GI symptoms occur. Still other clinicians will give folic acid 1 mg daily (except day MTX given) in all patients.

Infections

Hematotogic

aReactivation

aIntended

of hepatitis B, tuberculosis aOpportunistic infections—bacterial, fungal, mycobacterial aLive vaccines during MTX therapy “Radiation recall” with phototherapy, radiotherapy Methotrexate nodulosis

Miscellaneous Glucarpidase deficiency may ↑ MTX serum levels

for weekly use; severe toxicities if daily dosing aHematologic reactions (markedly ↓ risk with folic acid) If patient has severe hematologic reaction strongly consider leucovorin calcium

Hepatic & GI aGI—nausea, vomiting, diarrhea

(↓↓ risk with folic acid) aHepatotoxicity—hepatocellular liver injury, fibrosis/cirrhosis

Renal aAbnormal

renal function—↑ risk other toxicities mentioned earlier

Clinical use

Pregnancy Prescribing Status

Indications

Traditional US Food and Drug Administration rating—Category X

MTX is available as a 2.5-mg tablet or as 5.0-, 7.5-, 10-, and 15-mg tablets under the name of Trexall. We suggest using the 2.5 mg tablets to easily ascertain the dose being taken. In addition, by use of the 2.5 mg tablets only, one can titrate the dosage. MTX is also available in vials of sterile injectable solution, which may be used for intramuscular, intravenous (IV), intrathecal, intraarterial, or subcutaneous administration (2 mL vials with 2.5 mg/mL and 25 mg/mL available). More recently, MTX is now also available for subcutaneous injection via a prefilled autoinjector under the names of Otrexup (7.5–25 mg doses which escalate by 2.5 mg increments) and Rasuvo (7.5–30 mg doses, again escalating in increments of 2.5 mg). MTX is approved for use by patients with malignancies, including cutaneous lymphomas,23 along with approval for psoriasis vulgaris,24–28 and RA. However, it is widely used in dermatology practice for many other conditions, including bullous disorders, autoimmune connective tissue diseases (collagen vascular disorders), pityriasis rubra pilaris (PRP), pityriasis lichenoides et varioliformis acuta (PLEVA), sarcoidosis, and miscellaneous unrelated diseases. See Box 14.1 for Indications for MTX and Box 14.2 for the Drug Risks Profile of MTX.

Bone marrow suppression—aplastic anemia/pancytopenia Pneumonitis (especially RA patients) GI—diarrhea, ulcerative stomatitis, intestinal perforation (latter two virtually just with chemotherapy doses) Concomitant radiotherapy—soft tissue/bone necrosis

Warnings & Precautionsa

Cutaneous

colleagues22

Breastfeeding/pregnancy Immunodeficiency syndromes (overt/clinical)

Newer ratingb—CONTRAINDICATED

aUnder “Warnings

& Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid. bSee Chapter 65, Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings. GI, Gastrointestinal; Hgb, hemoglobin; MTX, methotrexate; RA, rheumatoid arthritis; WBC, white blood cell. Data from Facts & Comparisons eAnswers [online database]. St. Louis: Wolters Kluwer. [https:// www.wolterskluwercdi.com/facts-comparisons-online/].

US Food and Drug Administration-Approved Dermatologic Indications Psoriasis. The major clinical use of MTX in dermatology is in the therapy of psoriasis.24 The selection of the patient for the initiation of MTX therapy should be carefully considered. The benefits and risks of therapy, as well as available alternative therapies, should be discussed fully before MTX initiation. In general, the patient who is considered to be a MTX candidate should have debilitating disease that either is uncontrolled by conventional methods or is not likely to respond to more conservative therapies. Physicians should consider each patient

CHAPTER 14

• BOX 14.3 Indications for Methotrexate Therapy of

Psoriasis Erythrodermic psoriasis Psoriatic arthritis: not responsive to conventional therapy Pustular psoriasis: generalized or debilitating localized disease Psoriasis that adversely affects ability to maintain employment Extensive, severe plaque psoriasis: not responsive to conventional therapy (usually >20% surface involvement) Lack of response to phototherapy (PUVA and UVB) or systemic retinoids PUVA, Psoralens plus ultraviolet A; UVB, ultraviolet B.

on an individual basis, taking into account not only the characteristics of the disease, but also the socioeconomic aspects of and logistics for the individual. For example, it may be impractical for the patient to receive Goeckerman therapy, psoralens plus ultraviolet A (PUVA) therapy or narrow band ultraviolet B phototherapy because of job-related needs, or because they may not reside near a phototherapy facility. Similarly, retinoid therapy may be inappropriate because of hyperlipidemia or because the patient may be a woman of childbearing age. Cost issues may confront patients considered candidates for biologic therapies. Patients in our practices with recalcitrant psoriasis are presented with the risks and benefits of each of these treatment modalities and participate in the selection of the best therapeutic option for them. Roenigk and colleagues summarized the indications for the use of MTX in psoriasis,24 and these indications remain valid today25 (Box 14.3). The selection of the patient is made after the relative and absolute contraindications to the use of MTX are considered. The only absolute contraindications are pregnancy and lactation (see Box 14.2). The relative contraindications can be waived when the probable benefits of the therapy outweigh the potential risks in an individual patient. In general, 75% to 80% of psoriatic patients treated with MTX respond, typically demonstrating an initial response within 1 to 4 weeks. Full therapeutic benefit usually occurs within 2 to 3 months. A randomized trial demonstrated that 60% of MTX-treated patients reached a PASI (Psoriasis Area Severity Index)-75 score with 12 weeks of therapy at a dose of 15 to 20 mg weekly. This was not statistically different from cyclosporine; however, this study was not blinded to the patients, as they all knew that they were receiving an active therapy.26 In this study, there was a higher dropout rate in those treated with MTX. In contrast, a blinded study comparing MTX with adalimumab demonstrated fewer patients with a PASI-75 response (36% for MTX at 12 weeks), whereas 80% of those treated with adalimumab had this level of response versus only 19% of those treated with placebo.27 A recent literature review of cost efficacy of systemic treatments for psoriasis, found MTX to be the most cost effective to achieve a PASI-75 response with a monthly cost of US$794.05 to US$1502.01.29 Specifics regarding dosing and follow-up of the psoriatic patient are addressed in the Monitoring Guidelines and Therapeutic Guidelines sections of this chapter.

Off-Label Dermatologic Uses Other Proliferative Disorders. MTX has been reported to be useful for several other conditions. Patients with other presumed epidermal proliferative diseases, such as PRP,30–32 PLEVA,33 pityriasis lichenoides chronica (PLC) and Reiter disease,34 responded favorably to MTX. PRP seems to respond less well to MTX than

Methotrexate

161

does psoriasis. In general, the doses necessary to control PRP are 1.5 to 2 times higher than those necessary for control of psoriasis with a similar amount of involved body surface area. Furthermore, anecdotal reports historically suggested that for patients with PRP, the drug should be administered on a daily low-dose regimen rather than a weekly basis. An important disadvantage of this daily-dosage regimen, compared with the same total weekly given over 24 hours, is an increased risk of hematologic toxicity. MTX has only a secondary role in the treatment of PRP with the availability and efficacy of retinoids and possibly TNF-α antagonists. At times, MTX is used concomitantly with acitretin for patients with PRP. When this occurs, the treating physician will likely be contacted by insurance company pharmacy managers warning about the potential for enhanced hepatotoxicity. Thus a discussion with the patient should occur regarding this potential interaction. Exquisitely small doses of MTX (as little as 2.5–5 mg weekly) often can be used to control the disease process in patients with PLEVA and PLC.33 Reiter disease can at times be controlled with MTX. For this disease, the doses necessary are slightly higher than the doses for psoriasis, and the drug can be beneficial for both the rheumatologic and the cutaneous aspects.34 MTX therapy can also improve psoriatic arthritis and is FDA approved for use in conjunction with TNF-α antagonists. Immunobullous Dermatoses. Diseases of presumed immunologic origin may also respond to MTX. Specifically, bullous diseases, such as pemphigus,35,36 bullous pemphigoid (BP),36–40 cicatricial pemphigoid,41 and epidermolysis bullosa acquisita, may respond.42 Paul and associates37 have described their experience in elderly patients with BP. These patients must be treated cautiously because of the decreased renal function commonly present in patients over 70 years of age. Bara and coworkers38 reported their experience with 16 BP patients treated with MTX. Two patients had early toxicity and the therapy was discontinued. The remaining 14 patients, which included 4 patients with no other therapy and 10 patients with concomitant use of topical clobetasol propionate, were treated successfully. Overall, six of the responders were able to discontinue therapy without recurrence. Two patients had therapy-related AE, including colonic ulcerations and cytopenias, which precluded further therapy. Deruere and colleagues39 reported a similar experience with 18 patients with BP. Doses between 7.5 and 12.5 mg weekly were sufficient in 17 of their patients. All of their patients were initially treated with topical clobetasol as well. Kjellman and associates retrospectively analyzed their therapeutic regimens in 138 BP patients who were treated with prednisone alone, prednisone plus MTX or MTX alone. They found excellent responses with MTX, either with or without prednisone, and noted a statistically higher rate of remission at 2 years and improved survival in those patients treated with MTX.40 Therefore, MTX appears to be effective either as a solo agent or in conjunction with potent topical or systemic corticosteroids (CS) for BP patients. A review article by Gürcan and colleagues43 suggested that MTX is more efficacious in BP (94% clinical response) than pemphigus (82% clinical improvement). Ocular cicatricial pemphigoid is a sight-threatening disease generally treated with high-dose CS and cyclophosphamide. However, McCluskey and colleagues41 treated 17 patients who were between 63 and 81 years old with MTX in doses of 5 to 25 mg weekly. In this study, seven patients received topical CS and three patients were initially treated with dapsone. Complete control of ocular inflammation occurred in 11 of the 13 patients evaluated. Toxicity occurred in four patients but was mild and reversible upon cessation of therapy. The Gürcan review noted

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average clinical improvement in 88% of patients with ocular pemphigoid. Autoimmune Connective Tissue Diseases. Patients with autoimmune connective tissue diseases (collagen vascular diseases), such as dermatomyositis,44–48 lupus erythematosus,49–53 and scleroderma (including localized subsets),54–58 can respond well to MTX. MTX has been extremely useful to adults44–46 and children47 with dermatomyositis or polymyositis who either do not respond to CS or who develop CS-related AE. The drug is very effective in the control of the muscle disease. In patients with cutaneous dermatomyositis, doses higher than those for psoriasis or RA are generally needed. Often, up to 30 to 35 mg of MTX weekly has been used for dermatomyositis patients; however, the average weekly dose we use is 25 mg weekly. In dermatomyositis, the disease may be quantified. Thus clinicians can objectively measure a response by following the muscle strength or the levels of muscle enzymes. In addition, pulmonary involvement may also respond to MTX therapy.48 The drug is initiated at an empiric weekly dose, while the same dose of CS is maintained. The onset of noticeable improvement is generally within 4 to 8 weeks. Of the patients treated with MTX for dermatomyositis or polymyositis, about 75% will respond, and the dose of systemic CS can be significantly reduced. MTX has been reported to be effective in the treatment of cutaneous lupus erythematosus, both subacute and chronic.49,50 Wenzel and co-workers retrospectively analyzed their experience using IV MTX in 43 patients with ‘recalcitrant’ cutaneous lupus erythematosus.50 In a subsequent report, these same authors reported that subcutaneous administration is equally effective.51 Authors from Australia combined the use of MTX with cyclosporine in two patients who were nonresponsive to traditional therapy.52 Both localized scleroderma and progressive systemic sclerosis have reportedly improved with MTX therapy. However, the improvement is generally noted just for skin involvement, particularly in the early inflammatory stage.54–57 Kreuter and colleagues have reported the successful use of MTX often in combination with CS, in patients with widespread morphea and extragenital lichen sclerosus, but failed to note a response in patients with scleredema.57,58 The European Scleroderma observational study evaluated four protocols (MTX, mycophenolate, cyclophosphamide and no immunosuppressant) in the treatment of early diffuse cutaneous systemic sclerosis. MTX was administered orally or subcutaneously with a target does of 20 to 25 mg weekly. Skin scores improved in all treatment groups, but the least improvement was in the no immunosuppressant group.60 Vasculitis and Neutrophilic Dermatoses. Systemic vasculitis,61 including polyarteritis nodosa62 and cutaneous polyarteritis nodosa,63 has been successfully treated with MTX. Lee and coworkers have reported successful use of MTX in a patient with Kawasaki disease who failed IV immunoglobulin.64 Neutrophilic dermatoses, such as Behçet disease,63 pyoderma gangrenosum,65,66 and Sweet syndrome, may benefit from MTX therapy. The drug is most often used for these diseases as a means of sparing the patient from chronic high doses of CS. Other Dermatoses. Significant personal experience, and some literature experience, with MTX therapy for recalcitrant atopic dermatitis in adults suggests that this drug is a reasonable backup option for difficult cases.67,68 A recent report from Roekevisch and co-workers69 provides 2-year follow-up data in patients with atopic dermatitis treated with MTX versus azathioprine. The Scoring of Atopic Dermatitis (SCORAD) index decreased by 63% in the MTX group versus 53% in the azathioprine group,

but this difference was not statistically different. Common cold and hepatic enzyme abnormalities were more common in the MTX group, whereas influenza was more common in the azathioprine group. Klejtman and colleagues70 evaluated the effectiveness of MTX therapy in prurigo nodularis patients who had failed topical CS, oral antihistamines and/or phototherapy. With a median dose of MTX 15 mg weekly, an overall response rate of 91% was observed at 3 months and a complete response of 44% was noted. Anecdotal reports suggest that MTX is also beneficial for patients with cutaneous sarcoidosis,71–76 keloids,77 lymphomatoid papulosis,78 papulonecrotic Mucha-Habermann disease,79 keratoacanthomas,80 mycosis fungoides,81 Sézary syndrome,23,82 cutaneous Crohn disease (including patients with perianal fistulas),83,84 alopecia areata,85,86 and chronic idiopathic urticaria.87,88 MTX is uncommonly used in children for various dermatoses. Q14.4 Dadlani and Orlow reviewed its use in children and suggest that it may be safely used for psoriasis, atopic dermatitis, pemphigus, lupus erythematosus, dermatomyositis, and localized scleroderma.89 They also suggest that monitoring follow the guidelines developed by pediatric rheumatologists. Summary of ‘Off-Label’ Dermatology Indications. The use of MTX for ‘off-label’ indications for dermatomyositis, BP, localized scleroderma, cutaneous sarcoidosis, cutaneous polyarteritis nodosa, and the neutrophilic dermatoses has been beneficial. In general, for dermatomyositis and neutrophilic dermatoses, MTX must be used in maximum weekly doses ranging from 25 to 35 mg to achieve control of these diseases. For most other dermatoses, doses from 10 to 25 mg weekly will be adequate for a satisfactory clinical response. Monitoring techniques for these patients differs from the adult psoriasis guidelines only by not recommending repeated liver biopsies when liver-derived enzymes remain normal.

Adverse Effects Hepatotoxicity. The potential for hepatotoxicity in a patient treated with long-term MTX is an important consideration.24,90 Hepatotoxicity differs in the two large populations in which this drug is prescribed on a long-term basis: patients with psoriasis and patients with RA. The differences between these two populations have recently become more evident, and it is likely that the risk of hepatotoxicity in psoriatic patients relates to their tendency to be obese and to have coexisting steatohepatitis. However, over time it has become evident that even among patients with RA, MTX-related liver damage is possible.91 Although liver function tests may be abnormal in the presence of liver toxicity, they are frequently normal.92,93 Therefore it is essential to examine the histologic appearance of the liver during long-term therapy. The data on the risk of MTX-induced cirrhosis have varied widely, with reported frequencies from 0% to 25%.24,90 It appears that the risk of liver damage is low for patients whose cumulative dosage is less than 1.5 g.24 Q14.5 Although MTX cumulative doses at or above 4.0 g have been traditionally considered particularly risky for liver fibrosis and cirrhosis, recent studies with more careful patient selection to avoid important risk factors (renal insufficiency, diabetes mellitus, obesity, and excessive alcohol intake) demonstrated a much lower incidence of this important complication, even at high cumulative doses.94–96 It has been suggested that the combination of alcohol intake and MTX is associated with an increased risk of hepatotoxicity; however a recent literature review called this relationship into question and suggested that in the absence of other risk factors, including diabetes, obesity, hepatitis C, psoriasis, and lack of folic acid supplementation, the risk of severe liver

CHAPTER 14

disease is roughly 3% if alcohol intake is greater than 100 g per week (approximately 10 glasses of wine or spirits).97 A recent meta-analysis of randomized, controlled trials of patients prescribed MTX for RA, psoriasis, psoriatic arthritis or inflammatory bowel disease evaluated the risk of liver disease in 13,177 participants from a total of 32 studies (6877 on MTX and 6300 on comparator agents). The mean duration of therapy was 47 weeks. Liver-related events were common with a relative risk of 2.19 in the MTX-treated population. However, serious liver outcomes (hepatic failure, hepatic fibrosis, cirrhosis, or death from liver disease) were not increased in the MTX-treated group over the comparator group.98 The clinical course of the cirrhosis induced by MTX is often nonaggressive. In fact, many of the Scandinavian patients in one study continued MTX therapy without a deterioration in their liver histopathology.99 The patient who has an abnormal liver biopsy may with time experience a reversal of the findings, while off MTX therapy.92,99 Thus, it may be possible for that patient to resume MTX therapy after a period of time off the drug. Aithal and colleagues100 recently reported their analysis of 121 liver biopsies from 66 patients with psoriasis and concluded that advanced hepatic fibrosis is very infrequent, and further that routine use of serial liver biopsies had little impact on the care of these patients. However, in a study of sarcoidosis patients, Baughman and associates101 noted that liver enzyme abnormalities were common and that the only method of reliably detecting hepatotoxicity was the performance of a liver biopsy. Therefore, it appears to us that the monitoring guidelines should be liberalized for psoriasis, and in general the choice of whether to monitor with liver biopsy should be dependent upon the disease state being treated, the presence of concomitant diseases affecting MTX risk, the presence of patient behavioral characteristics (such as alcohol intake), and patient choice. Although liver biopsy is the gold standard for evaluating liver fibrosis, it is associated with a sampling error of 20% to 30%; and as an invasive procedure, there is risk of morbidity and mortality.98 A noninvasive test to diagnose MTX-induced hepatotoxicity would be ideal. Q14.6 Hepatic ultrasound may be useful according to one study,102 however other studies have reported the inability of ultrasound to discriminate fat from fibrosis.103,104 Radionuclide scans and the aminopyrine breath test are inadequate to screen for hepatotoxicity caused by MTX.103,105 The amino-terminus of type III procollagen peptide (PIIINP) is a serum test that may be of value in assessing ongoing hepatic fibrosis.106,107 The key limitation of PIIINP assessments is the lack of site specificity as to which organ is undergoing fibrosis; thus this test is not reliable in patients with significant psoriatic arthritis. Based on these various noninvasive tests, Zachariae made a strong plea to consider using tests, such as ultrasound, dynamic radionuclide scans, and the PIIINP assay to at least reduce (not eliminate) the number of liver biopsies required for patients on MTX therapy.108 A recent study from The Netherlands found that PIIINP assessment significantly lowered the number of liver biopsies to assess for MTX-related hepatotoxicity in patients with psoriasis. This study also supports the theory that other factors, such as obesity and fatty liver, play a role in liver fibrosis development in this patient group.109 However, the PIIINP test is not currently commercially available in the United States, although it is widely available in Europe. Tests are being developed to follow and aid in the management of patients with hepatitis B and C as well as nonalcoholic steatohepatitis (NASH). Bauer and others110 evaluated the NASH FibroSure test, in psoriatic patients receiving long-term MTX,

Methotrexate

163

as a noninvasive predictor of NASH and liver fibrosis. This retrospective, single center study provided data supporting the use of this test in monitoring psoriasis patients on long-term MTX, thereby limiting liver biopsies. Transient elastography (TE; also known as Fibroscan) may be another, noninvasive test to detect liver fibrosis in psoriasis patients. Talme and associates111 recently reported their data comparing TE measurements for liver stiffness with serologic markers of liver fibrosis (liver transaminases, platelet count and PIIINP). Among 201 psoriasis patients receiving MTX for greater than 24 months, 37.7% had liver stiffness, indicating mild fibrosis, whereas 9% had liver stiffness indicating severe fibrosis. Body mass index greater than 30 and diabetes were the strongest risk factors predicting liver fibrosis. In 8 of 11 patients with TE/Fibroscan measurements indicating severe liver fibrosis, subsequent liver biopsy confirmed grade III fibrosis.111 In the future these tests might have a role in following patients while on MTX. Although liver biopsy is the gold standard for the most accurate diagnosis of MTX-induced hepatic fibrosis and cirrhosis, a substantial controversy remains regarding the role of routine liver biopsies in monitoring patients receiving long-term MTX. For a full discussion on the pros and cons of percutaneous liver biopsies see the Monitoring Guidelines section and Table 14.2 in this chapter. Pulmonary Toxicity. In rare instances, pulmonary toxicity, such as acute pneumonitis, can occur.112–117 This pulmonary toxicity is idiosyncratic, can occur with extremely small doses of MTX, and can be life-threatening if MTX is not stopped. In addition, some patients develop a more gradual pulmonary toxicity manifested by pulmonary fibrosis on chest x-ray. Routine screening chest x-ray studies and pulmonary function testing are not useful in the detection or prevention of pulmonary toxicity.116 The great majority of the pulmonary toxicity reported has occurred in patients with RA, with a prevalence of up to 5% reported in these patients. MTXinduced pneumonitis has infrequently been reported in psoriasis patients.116 A chest x-ray should be done only if the patient develops symptoms suggesting pneumonitis. Hematologic Effects. Hematologic toxicity, such as pancytopenia, presents the greatest potential for loss of life as a result of MTX. Q14.3 By far the greatest amount of data on pancytopenia caused by MTX is found in the rheumatology literature.118–122 In most of these studies, the risk of pancytopenia was significantly reduced by routine folic acid supplementation. There are a number of definable risk factors for pancytopenia in these patients that are all essentially avoidable (Table 14.3). There are far fewer reports of pancytopenia in dermatologic patients.123–125 However, one identifiable and avoidable risk factor is poor renal function. Several reports of pancytopenia, including one that was associated with a fatal outcome, have appeared involving psoriatic patients on hemodialysis.126 It is not clear whether the risk for pancytopenia in psoriasis is less than the risk for RA patients, or whether the dermatology community has been less systematic in collating and reporting this important complication. Either way, all clinicians should routinely: 1. Be vigilant about potential drug interactions with MTX (see Table 14.1), particularly those involving trimethoprim/sulfamethoxazole (TMP-SMX) combinations,127,128 and to a lesser degree nonsteroidal anti-inflammatory drugs (NSAID)129 in combination with MTX; and 2. Q14.3 Consider supplementing MTX treatment with 1 to 5 mg daily of folic acid (folate), regardless of whether the patient is experiencing nausea or other GI AE.24,130,131

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TABLE Major Liver Biopsy Studies—Fatal Complications Blind Versus Ultrasound-Guided Liver Biopsies 14.2

Author

Study Year

Biopsy #

Deaths

DeathsBaseline MTX Biopsy

Deaths (A)

Deaths (B)

Deaths (C)

Deaths (D)

Deaths (E)

Blind Liver Biopsies Piccicino173

1986

68,276

6

None

3

3

–

–

–

Wildhirt174

1981

19,563

0

None

–

–

–

–

–

Van Thiel175

1993

12,695

0

None

–

–

–

–

–

McGill176

1990

9212

10

1

1

6

–

–

2

Sherlock177

1985

6379

2

None

–

–

–

1

1

Ultrasound-Guided Liver Biopsies Lang178

1999

3670

0

None

–

–

–

–

–

Buscarini179

1990

2091

0

None

–

–

–

–

–

Drinković180

1996

1750

2

None

–

1

1

–

–

Columbo181

1988

1192

0

None

–

–

–

–

–

Bret182

1988

1060

1

None

–

–

–

–

–

Five largest studies evaluating each liver biopsy technique. (A) Biopsy deaths attributed to cirrhosis and portal hypertension. (B) Biopsy deaths attributed to liver metastasis. (C) Biopsy deaths attributed to primary hepatic carcinoma. (D) Biopsy deaths attributed to a coagulation defect. (E) Biopsy deaths attributed to acute hepatitis.

TABLE Risk Factors for Methotrexate Pancytopenia118–122 14.3

Risk Factor

Comments

More Common Risk Factors for Methotrexate Pancytopenia Drug interactions

Can occur at any time of methotrexate therapy; especially TMP/SMX and NSAID

Renal disease

Even slight increase in creatinine to 1.5–2.0 range an important risk factor

Elderly patients

Vast majority of cases in patients aged >65–70 years; largely caused by reduced renal function

No folate supplementation

In studies cited, pancytopenia virtually never occurred with folate supplementation

Less Common Risk Factors for Methotrexate Pancytopenia Daily methotrexate dosing

In current era, primarily inadvertent given unique once weekly normal dosing scheme

First 4–6 weeks of therapy

In absence of drug interactions or recent major illness, most cases early in therapy

Albumin 110,000 patients for all biopsy indications) occurred with a pretreatment MTX liver biopsy using the blind technique.176 Overall, most patients strongly prefer the greater physical comfort and the psychologic reassurance of the ultrasound-guided technique. On the other hand, deaths attributed to MTX-induced cirrhosis have occurred in patients with psoriasis. These deaths may be avoidable with proper surveillance.183 In addition, a case series regarding patients who developed severe cirrhosis and subsequently underwent liver transplantation after receiving long-term MTX, in the absence of liver biopsy surveillance, was published.184 Q14.11 There are many situations in which pretreatment liver biopsy may not be necessary. These clinical scenarios include the following: 1. Not all patients with psoriasis improve with MTX; 2. Furthermore, some patients cannot tolerate the drug even in small doses; or 3. Long-term MTX may not be required after an impressive early clinical response. In these instances, performing a pretreatment liver biopsy has placed the patient at risk without any foreseeable benefit. Therefore many physicians are postponing the initial biopsy until at least the third to sixth month of therapy for patients with potential liver disease, or to a cumulative dose of 1500 mg in otherwise healthy patients with psoriasis and normal liver function testing. It is still imperative that a full discussion with the patient takes place, so that the patient understands that a biopsy will be needed at some time in the future. An advantage of a pretreatment or delayed baseline MTX liver biopsy is that it impresses on patients the serious nature of the agent with which they are about to be treated. Q14.11 There are several other instances in which a pretreatment MTX liver biopsy is necessary, although subsequent point 5 is important to consider. 1. For patients with a personal or familial history of liver disease, a liver biopsy before therapy is helpful; 2. Similarly, for those patients with a history of exposure to known hepatotoxins, including alcohol or IV drugs, specific baseline knowledge of liver histology is important; 3. Patients with diabetes, hyperlipidemia or obesity are presumed to be at greater risk for liver toxicity, and pretreatment biopsies may be deemed necessary; 4. Finally, in patients with abnormal baseline liver function tests or serologic tests for hepatitis, a liver biopsy before receiving the first dose of MTX is usually recommended; and 5. It is quite reasonable to strongly consider avoiding MTX therapy altogether in the patients mentioned here, given the significantly increased risk of hepatotoxicity in, and efficacious alternate therapies for these patient populations.

CHAPTER 14

Current dermatology guidelines offer the option of waiting until 1 to 1.5 g cumulative MTX dose before performing a ‘baseline’ liver biopsy on relatively low-risk patients.24 From references cited in these current guidelines, a substantial portion of all psoriasis patients who developed cirrhosis had full-blown cirrhosis present at the 1.5 g cumulative dose (frequently with completely normal ‘liver function tests’). The need for repeated liver biopsies is based on the total dose taken by the patient.24 The cumulative dose should be periodically calculated and recorded in the patient’s medical record to more effectively deal with the discussion of the need for a liver biopsy. The current guidelines from a 2009 National Psoriasis Foundation consensus conference deem a pretreatment liver biopsy not necessary in low risk patients, with the first biopsy at 3 to 4.5 g of total MTX and subsequent biopsies to be considered after each subsequent accumulated 1.5 g total dose.170 The time needed to reach this level of intake varies, depending on the weekly dose. A prior dermatology resident (Tom Eads MD) of the editor (SEW) developed a rapid method of determining the timing of the need for liver biopsy at the suggested 1.5-g intervals. A very close approximation of the interval can be determined by dividing the number ‘12’ by the number of 2.5 mg capsules of MTX taken weekly—this gives the number of years to reach a 1.5 g cumulative dose. For example, if the patient is taking four 2.5-mg capsules weekly, the interval between liver biopsies is 12/4 (3 years). If the patient is taking six 2.5-mg capsules weekly, the interval between liver biopsies is 12/6 (2 years). Continuation or discontinuation of MTX is based on liver biopsy findings (Table 14.4). The following recommendations have been proposed by Roenigk and colleagues:24 1. Patients with grade I or II changes may continue to receive MTX therapy. 2. Patients with grade IIIA changes may continue to receive MTX therapy, but should have another liver biopsy after approximately 6 months of continuous therapy. 3. Patients with grades IIIB and IV should not be given further MTX except in exceptional circumstances, with careful followup of liver biopsies. The discrimination of grade IIIA from grade IIIB changes is somewhat subjective, despite the impact on the decision-making process. Equally important is the trend of histologic changes when previous liver biopsies are compared. Finally, influenced by an editorial concerning liver biopsy frequency and noninvasive testing options,108 it is reasonable to suggest that a possible ‘middle ground’ might exist, as follows. If a given patient has had two consecutive liver biopsies (grade II changes at most) at traditional intervals, it seems very reasonable to alternate a noninvasive test of liver structure and/or fibrosis (liver scan, PIIINP—where available—NASH Fibrosure, Fibroscan or ultrasound) with a liver biopsy. The net effect of alternating these tests is that after two normal liver biopsies (grade II changes only), the occasional patient on very long-term MTX therapy would have a liver biopsy every 3.0 g of MTX, and undergo a noninvasive test for hepatotoxicity half-way between liver biopsies. Editor’s Note. (SEW) - At our institution and at many others, the Fibroscan has quickly evolved to the primary screening test for MTX-induced liver disease in conjunction with LFT. The first use of the Fibroscan is typically after 1-year of MTX and may be repeated yearly. Comanagement with a GI doc in all patients, and in some patients with high “liver stiffness” result in a percutaneous liver biopsy. The net result is a significant reduction of liver biopsies in MTX patients.

Methotrexate

167

TABLE Classification of Liver Biopsy Findings 14.4

Biopsy Grade

Liver Histopathologic Findings

Grade I

Normal; fatty infiltration—mild; portal inflammation—mild

Grade II

Fatty infiltration—moderate to severe; portal inflammation—moderate to severe

Grade IIIA

Fibrosis—mild

Grade IIIB

Fibrosis—moderate to severe

Grade IV

Cirrhosis

Modified from Roenigk HH Jr, Auerbach R, Maibach HI, Weinstein GD. Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol. 1988;19(1 Pt 1):145–156.

Laboratory Monitoring. The patient should be monitored closely during the initial phases of therapy with frequent CBC (usually within 1–2 weeks after beginning therapy or escalating the dose), liver function panels, and serum creatinine measurements during the initial phase of therapy, regardless of the disease for which MTX is being used. If the white blood cell count (WBC) is less than 3500/mm3, the platelet count is less than 100,000/mm3, or there is an increase over twice the upper normal value for liver transaminase levels, discontinue or reduce the dosage of MTX. If the laboratory abnormality has resolved, the drug may be restarted at a lower dose after a 2 to 3 week rest. After the first month of therapy, this laboratory monitoring can be gradually reduced in frequency to a range of every 3 to 4 months. More frequent monitoring is necessary if the dose is being escalated, if there is an intercurrent illness, or if additional systemic therapy with other drugs is begun. This is particularly important if the additional drug (such as acitretin) has an inherent potential for liver toxicity or renal toxicity. Published guidelines recommend hematologic laboratory follow-up every 1 to 3 months.24,170 In practice, it is rare to develop an abnormal WBC or platelet count after the first few months of therapy on a constant or tapering MTX dose. An exception is the potential risk for pancytopenia to occur at any stage of therapy, when potential drug interactions are not recognized. The potential risk is greatest with the addition of either TMP-SMX or a NSAID to a patient already receiving a full dose of MTX.127–129 Furthermore, late hematologic complications occasionally occur because of patient errors, in which MTX is inadvertently taken on a daily basis.185

Therapeutic Guidelines Once the decision has been made to administer MTX, the next step is to decide on the dosage and the route of administration. For patients with psoriasis, oral weekly doses are usually effective and reasonably well tolerated. An occasional patient who is poorly compliant may be treated with weekly intramuscular MTX, as may the patient who develops nausea from oral, but not parenteral administration. Q14.12 There are two methods of weekly administration of oral MTX: a single weekly dose and three divided doses over a 24-hour period each week. The divided-dose regimen consists of taking the medication on a

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Systemic Immunomodulatory Drugs

schedule, such as 8 AM and 8 PM on the first day and 8 AM on the second day; with the development of the dose pack, sold under the trade name Rheumatrex (3 2.5-mg tablets per dose pack; under this name, there are also 4, 5, and 6 tablets per dose pack), this schedule may be easier to explain. The rationale behind this schedule relates to the presumed cell cycle kinetics in psoriasis. However, the two methods of administration are equally effective and have similar toxicity. Given the simplicity of a single weekly dose, with all other issues equal, this would be the most logical dosing scheme. Either way, the patient should always be reminded to carefully adhere to the unique weekly schedule of MTX administration (whether the physician is using a single- or a 3-dose regimen). Significant hematologic complications of inadvertent daily MTX overdosing are more likely.185 Intramuscular and subcutaneous dosing of MTX results in rapid and complete absorption and less variable exposure than oral dosing. Because systemic absorption of oral MTX plateaus at doses of equal to or greater than 15 mg per week, rheumatologists have begun to embrace subcutaneous administration in their patients.186,187 However, there is a lack of evidence-based studies evaluating the use of subcutaneous MTX in the treatment of patients with psoriasis. The authors believe in selected patients two 15 mg doses in a day, thus 30 mg in a day, could be used each week. The initial dose should be fairly conservative to prevent myelosuppression. In general, a test dose of 5 to 10 mg is given, and a CBC and LFT are taken 6 to 7 days later. The dose is gradually escalated (2.5–5 mg/week) to a level that provides reasonable benefit without noticeable toxicity. Patients receiving intramuscular or IV MTX are able to tolerate higher doses because of more rapid renal clearance. One can measure the response to the drug by quantifying the area of surface involvement or by evaluating the characteristics of an individual lesion, such as a scale, erythema, or elevation. In general, patients with psoriasis are able to achieve benefits at 10 to 15 mg/week. The total weekly dose rarely exceeds 30 mg. When maximal benefit is reached, the MTX may be tapered by 2.5 mg/week to determine the lowest possible dosage that maintains disease control. For patients treated with intramuscular MTX, it may be more convenient to taper by increasing the interval between doses to 2 weeks or more. The dosage and the schedule of administration for other disorders may differ from those recommended for psoriasis. These differences have been discussed previously.

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References* 12. Jeffes 3rd EW, McCullough JL, Pittelkow MR, et al. Methotrexate therapy of psoriasis. Differential sensitivity of proliferating lymphoid and epithelial cells to the cytotoxic and growth-inhibitory effects of methotrexate. J Invest Dermatol. 1995;104(2):183–188. 20. Salim A, Tan E, Ilchyshyn A, Berth-Jones J. Folic acid supplementation during treatment of psoriasis with methotrexate: a randomized, double-blind, placebo-controlled trial. Br J Dermatol. 2006;154(6):1169–1174. 50. Wenzel J, Brähler S, Bauer R, Bieber T, Tüting T. Efficacy and safety of methotrexate in recalcitrant cutaneous lupus erythematosus: results of a retrospective study in 43 patients. Br J Dermatol. 2005;153(1):157–162. 58. Kreuter A, Tigges C, Gaifullina R, Kirschke J, Altmeyer P, Gambichler T. Pulsed high-dose corticosteroids combined with low-dose methotrexate treatment in patients with refractory generalized extragenital lichen sclerosus. Arch Dermatol. 2009;145(11):1303–1308. 132. Kuitunen T, Malmström J, Palva E, Pettersson T. Pancytopenia induced by low-dose methotrexate. A study of the cases reported to the finnish adverse drug reaction register from 1991 to 1999. Scand J Rheumatol. 2005;34(3):238–241.

* Only a selection of references are printed here. All other references in the reference list are available online at www.expertconsult.com.

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141. Ishida M, Hodohara K, Yoshii M, et  al. Methotrexate-related Epstein-Barr virus-associated lymphoproliferative disorder occurring in the gingiva of a patient with rheumatoid arthritis. Int J Clin Exp Pathol. 2013;6(10):2237–2241. 142. Horie N, Kawano R, Kaneko T, Shimoyama T. Methotrexaterelated lymphoproliferative disorder arising in the gingiva of a patient with rheumatoid arthritis. Aust Dent J. 2015;60(3): 468–411. 143. Shapiro N. Diffuse large B-cell lymphoma of the gingiva in a patient on long-term methotrexate being treated for psoriasis. Compend Contin Educ Dent. 2015;36(6):426–428. 144. Maderal AD, Malone JC, Callen JP. Methotrexate-associated B-cell lymphoproliferative disease in a patient with cutaneous T-cell lymphoma. JAMA Dermatol. 2018;154(4):490–492. 145. Bailin PL, Tindall JP, Roenigk Jr HH, Hogan MD. Is methotrexate therapy for psoriasis carcinogenic? A modified retrospective-prospective analysis. JAMA. 1975;232(4):359–362. 146. Nyfors A, Jensen H. Frequency of malignant neoplasms in 248 long-term methotrexate-treated psoriatics. A preliminary study. Dermatologica. 1983;167(5):260–261. 147. Polesie S, Gillstedt M, Sönnergren HH, Osmancevic A, Paoli J. Methotrexate treatment and risk for cutaneous malignant melanoma: a retrospective comparative registry-based cohort study. Br J Dermatol. 2017;176(6):1492–1499. Other Adverse Effects 148. Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA, Tugwell P. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis: a meta-analysis of randomized controlled trials. J Rheumatol. 1998;25(1):36–43. 149. Källén B. The teratogenicity of antirheumatic drugs – what is the evidence? Scand J Rheumatol Suppl. 1998;107:119–124. 150. Lewden B, Vial T, Elefant E, et al. Low dose methotrexate in the first trimester of pregnancy: results of a French collaborative study. J Rheumatol. 2004;31(12):2360–2365. 151. Morris LE, Harrod MJ, Menter MA, Silverman AK. Methotrexate and reproduction in men: case report and recommendations. J Am Acad Dermatol. 1993;29(5 Pt 2):913–916. 152. Gromnica-Ihle E, Krüger K. Use of methotrexate in young patients with respect to the reproductive system. Clin Exp Rheumatol. 2010;28(5 suppl 61):S80–S84. 153. Beghin D, Cournot MP, Vauzelle C, Elefant E. Paternal exposure to methotrexate and pregnancy outcomes. J Rheumatol. 2011;38(4):628–632. 154. Armstrong RB, Poh-Fitzpatrick MB. Methotrexate and ultraviolet radiation. Arch Dermatol. 1982;118(3):177–178. 155. Guzzo C, Kaidby K. Recurrent recall of sunburn by methotrexate. Photodermatol Photoimmunol Photomed. 1995;11(2):55–56. 156. Adkins SA, Byrd JC, Morgan SK, Ward FT, Weiss RB. Anaphylactoid reactions to methotrexate. Cancer. 1996;77(10):2123– 2126. 157. Hellier I, Bessis D, Sotto A, Margueritte G, Guilhou JJ. High dose methotrexate induced bullous variant of acral erythema. Arch Dermatol. 1996;132(5):590–591. 158. Goerttler E, Kutzner H, Peter HH, Requena L. Methotrexateinduced papular eruption in patients with rheumatic diseases: a distinctive adverse cutaneous reaction produced by methotrexate in patients with collagen vascular diseases. J Am Acad Dermatol. 1999;40(5 Pt 1):702–707. 159. Harrison PV. Methotrexate-induced epidermal necrosis. Br J Dermatol. 1987;116(6):867–869. 160. Kazlow DW, Federgrun D, Kurtin S, Lebwohl MG. Cutaneous ulceration caused by methotrexate. J Am Acad Dermatol. 2003;49(2 suppl 2):S197–S198.

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15 Azathioprine DANIEL GROVE AND SAHAND RAHNAMA-MOGHADAM

QUESTIONS Q15.1 What are the pros and cons of ordering baseline testing for thiopurine methyltransferase (TPMT) enzyme activity (phenotype) before initiating azathioprine therapy? (Pg. 170x2) Q15.2 What is a general guide for interpretation of the laboratory testing for the genotype for TPMT activity? (Pg. 170) Q15.3 Concerning azathioprine drug interactions, (1) what is the most important drug interaction and its mechanism, and (2) what are several other important interactions? (Pgs. 171, 176) Q15.4 Based on TPMT enzyme levels (phenotype testing), what is the appropriate azathioprine dose in mg/kg/day for a patient with (1) a normal enzyme level, (2) an intermediate enzyme level, and (3) a low enzyme level? (Pg. 172) Q15.5 Concerning the azathioprine mechanisms of action, (1) what is the most general theory on the mechanism, and (2) why is the drug likely effective treating immunobullous diseases? (Pg. 172)

Q15.6 How does the incidence of lymphoproliferative malignancies and cutaneous squamous cell carcinomas differ in patients receiving azathioprine for dermatologic diseases, rheumatoid arthritis, and solid organ transplantation? (Pg. 173) Q15.7 What is a reasonable lower limit for a white blood cell count during azathioprine therapy and what are some measures clinicians can use when this lower limit is passed? (Pg. 174) Q15.8 What are the important clinical features of the hypersensitivity syndrome occasionally induced by azathioprine? (Pg. 175) Q15.9 Concerning azathioprine gastrointestinal adverse effects, (1) what are the most common symptoms, and (2) what are several simple measures to decrease these symptoms? (Pg. 175) Q15.10 Why is hepatic monitoring of importance in following patients receiving azathioprine therapy? (Pg. 176)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R 6-MP 6-Mercaptopurine 6-TG 6-Thioguanine CBC Complete blood count FDA US Food and Drug Administration GI Gastrointestinal HGPRT Hypoxanthine-guanine phosphoribosyl transferase IBD Inflammatory bowel disease LCV Leukocytoclastic vasculitis LFT Liver function test

RBC Red blood cell RCT Randomized controlled trial SCC Squamous cell carcinoma SLE Systemic lupus erythematosus TNF Tumor necrosis factor TPMT Thiopurine methyltransferase WBC White blood cell XO Xanthine oxidase

Introduction

Paramount to the safe and efficacious use of azathioprine is an understanding of the metabolism of this drug, specifically, awareness of the genetic polymorphism of an enzyme, thiopurine methyltransferase (TPMT) and pretreatment phenotypic testing of this enzyme. Pretreatment TPMT enzyme testing may avoid catastrophic myelosuppression and guide proper dosing, but regular complete blood counts (CBC) and liver function tests (LFT) are still needed to monitor for myelosuppression and hepatotoxicity throughout the course of treatment. Adverse effects (AE) of azathioprine include myelosuppression, gastrointestinal (GI) symptoms, hypersensitivity reaction, infections, pancreatitis, lymphoproliferative malignancy, and cutaneous squamous cell carcinomas (SCC).

Azathioprine (Imuran, Azasan) (Table 15.1) was synthesized in 1959 from its parent drug 6-mercaptopurine (6-MP), and became drug of choice for organ transplantation during the 1960s and 1970s. During this time, it became apparent that azathioprine had not only immunosuppressant, but also anti-inflammatory properties. Rheumatologists, gastroenterologists, neurologists, and dermatologists began using azathioprine for a wide variety of inflammatory and autoimmune diseases. Dermatologists use azathioprine for the treatment of immunobullous diseases, atopic dermatitis, and actinic dermatitis as well as other inflammatory and autoimmune dermatoses.

169

170

Systemic Immunomodulatory Drugs

PA RT I V

Pharmacology Table 15.2 contains the key pharmacologic concepts for azathioprine. Figure 15.1 shows the structure of azathioprine.

Absorption and Distribution After oral administration, more than 88% of azathioprine is absorbed through the GI tract.1 Azathioprine does not cross the blood–brain barrier, but easily crosses the placenta and into mammary glands. The peak plasma levels occur in less than 2 hours. Azathioprine is rapidly and extensively metabolized. The active metabolite 6-thioguanine (6-TG) slowly accumulates in tissues and eventually provides maximal clinical immunosuppression at around 8 to 12 weeks, using traditional, somewhat conservative, dosage schemes.2

Metabolism and Excretion Three Pathways for Azathioprine Metabolism (Table 15.3, Fig. 15.2). Azathioprine is rapidly converted to 6-MP upon absorp-

tion; conceptually, azathioprine is a ‘prodrug’. This conversion occurs mainly in erythrocytes. Q15.1 The fate of 6-MP is determined by one of the following three competing pathways: TABLE Azathioprine 15.1

Generic Name

Azathioprine

Trade names

Imuran, Azasan

Date released

1959

Drug formulations

50 mg, 75 mg, 100 mg 50 mg tablets are scored 100 mg vials

Drug dosing—empiric

Up to 2–2.5 mg/kg daily

Drug dosing by TPMT level and genotype High TPMT >15.1–26.4 U/mL or homozygous wild type Medium TPMT 6.3–15 U/mL or heterozygous wild type Low TPMT azithromycin

CYP3A4 inhibitors which ↑ CsA drug levels and resultant toxicity—renal, HBP, lipids, etc.

Azole, triazole antifungals

Ketoconazole >> itraconazole > fluconazole (only >200 mg daily)

Same

Calcium channel blockers

Diltiazem, verapamil

Same (all other CCB are just CYP3A4 substrates)

Fluoroquinolones

Ciprofloxacin

Same

HIV-1 protease inhibitors

Ritonavir, indinavir >> saquinavir, nelfinavir

Same

Nutritional products

Grapefruit, grapefruit juice

Same

Miscellaneous (CYP3A4 inhibitors)

Danazol, ticlopidine

Same

Rifamycin antibacterials

Rifampin, rifabutin

CYP3A4 induction with resultant ↓ CsA drug levels and loss efficacy; this effect takes 1–2 weeks; most important with solid organ transplantation, more severe autoimmune conditions

Aromatic anticonvulsants

Phenytoin, carbamazepine, phenobarbital

Same

Aminoglycosides, others

Gentamicin, tobramycin, TMP/SMX, vancomycin

Potentially renal toxic drugs which in combination ↑ risk of CsA renal toxicity (possibly also HBP)

Antifungals (misc.)

Amphotericin B

Same

Anti-inflammatory

NSAID; indomethacin, naproxen, etc.

Same

Immunosuppressants

Wide variety—relatively uncommon to have these SAE in dermatology

Biologics, JAK inhibitors, traditional (azathioprine, mycophenolates, etc.), chemotherapy, higher dose CS with risk of severe infections and/or myelosuppression

Miscellaneous

Drug groups which can ↑ potassium

ACE inhibitors, angiotensin II receptor blockers, potassiumsparing diuretics, potassium supplements

Miscellaneous

CsA can ↓ renal clearance

Digoxin, lovastatin, prednisolone with resultant ↑ drug levels

Vaccines

Live, attenuated (e.g., Zostavax)

Immunize at least 2 weeks before CsA; risk of (1) low/no immune response, (2) disseminated VZV (or other severe infections depending on vaccine)

Corticosteroids

Dexamethasone, methylprednisolone

CYP3A4 substrates which may ↑ CsA drug levels through unknown mechanism

Hormonal contraceptives

Various estrogens, progesterones

Same

Lower-Risk Drug Interactions

The dramatic increase in number of drug interactions in medicine requires some degree of selectivity in these tables (common usage, relative risk, focus on outpatient treatment). aOverall highest-risk drug interactions indicated in bold italics. ACE, Angiotensin converting enzyme; CCB, calcium channel blockers; CsA, cyclosporine A; CYP, cytochrome P-450; HBP, high blood pressure; HIV, human immunodeficiency virus; JAK, janus kinase; NSAID, nonsteroidal anti-inflammatory drug; SAE, serious adverse effect; TMP/SMX, trimethoprim/ sulfamethoxazole; VZV, varicella zoster virus. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications; 2019. (http://www.hanstenandhorn.com/).

For any patient in whom the serum creatinine rises by at least 50% above baseline, CsA should be discontinued until the serum creatinine returns to baseline. Clinicians should exercise caution in restarting CsA in this clinical scenario. Therapeutic Guidelines. In evaluating patients for CsA therapy, key issues include patient selection, preliminary work-up, and continued monitoring throughout therapy. Baseline Assessment. The patient should be carefully instructed regarding the nature and implementation of CsA

treatment. The short-term use of CsA, ideally for 3 to 6 months, 12 to 24 months at most, with regular laboratory and in-person blood pressure monitoring needs to be explained to the patient before starting therapy, to ensure compliance. A thorough history and physical examination should be conducted to rule out the existence of any active infection or tumor, with careful attention being paid to measurement of blood pressure. Before initiating therapy, laboratory and blood pressure evaluation should be done as outlined in the previous section. This

CHAPTER 17

• BOX 17.5 Cyclosporine Monitoring

Guidelines6,13,82,83,94 Baseline: Examination • Complete history and physical examination (to rule out active infections, malignancy) • Two baseline blood pressures at least a day apart

Laboratory • Baseline serum creatinine levels (two baseline creatinine values at least a day apart) • Other baseline renal evaluation—Blood urea nitrogen (BUN) • Complete blood count (CBC)a and liver function tests (especially SGOT/AST- Aspartate Aminotransferase, and SGPT/ALT-Alanine Aminotransferase)a • Fasting lipid profile—triglycerides, cholesterol, high-density lipoprotein (HDL) cholesterol • Other laboratory tests: magnesium (may decreaseb), potassium (may increase) uric acid (mainly relevant for patients at risk for gout)

Follow-Up: Examination • Re-evaluate the patient every 2 weeks for 1–2 months, then every 4–6 weeks while on cyclosporine if all parameters are within normal limits. • Blood pressure checked at each visit

Laboratory • Laboratory surveillance every 2 weeks for the first 1–2 months, then monthly while on cyclosporine • Renal function—serum creatinine, BUN, urinalysis • CBC and liver function tests (especially SGOT/AST and SGPT/ALT)a • Lipids—triglycerides, cholesterol • Other laboratory tests—magnesium, potassium, uric acid

Indicated Infrequently On Selected Patients • Serum cyclosporine A (CsA) level,c creatinine clearance (consider if 1–2 years therapy), kidney biopsy (very rarely) More frequent surveillance is needed if laboratory values are abnormal or with high-risk patients. aCBC and liver function tests (including transaminases) very seldom affected by cyclosporine. bSerum magnesium may not be relevant if CsA usage is limited in duration. cConsider doing trough cyclosporine drug levels if inadequate clinical response or for suspected drug interactions or noncompliance.

evaluation ideally should include two separate blood pressure evaluations and two serum creatinine levels checked at least 24 hours apart. Dosage and Treatment Regimens. There are two schools of thought regarding the proper approach to dosing CsA. One advocates the initial use of a high-dose regimen, with gradual transition to a lower dosage, and the other advocates the initial use of a low dose, with upward dose adjustment as indicated. More important than any guidelines or ‘schools of thought,’ the initial dosage of CsA for the treatment of psoriasis should depend on the clinical state of the patient being treated. For patients with severe, inflammatory flares of psoriasis or truly recalcitrant cases (psoriasis that has failed to respond to many other treatment modalities), where rapid improvement is critical, the authors recommend starting with the maximum dermatologic CsA dosage of 5 mg/kg daily administered in two divided doses, because 3 mg/kg per day is often not adequate even as a maintenance dose in these cases of severe psoriasis.8 As soon as the patient is no longer in great distress, the authors recommend maintaining that effective dose for at least 2 to 3 months, and then the dosage of CsA can be reduced in

Cyclosporine

195

decrements of 1 mg/kg daily every other week until the minimum effective dosage for maintenance therapy for that patient is defined. On the other hand, for patients with generalized but relatively stable plaque-type psoriasis, or for cases where the severity lies between moderate and severe, it is reasonable to start with a relatively low dose, typically 2.5 to 3 mg/kg per day. If improvement in psoriasis has not occurred by 1 month, it is important to remember to increase the CsA dosage in increments of 0.5 to 1 mg/kg day every 2 weeks as necessary, but not to exceed the maximum dose of 5 mg/kg daily. Both the rate of clearance and the overall success rate are related to the starting dose. It has been well demonstrated that 5 mg/kg per day dosing is on average much more efficacious, in terms of both rapidity of the onset of therapeutic effect and the probability of clearing, than lower dosages such as 1.25 or 2.5 mg/kg per day (Figs 17.4 and 17.5).9 If there is insufficient response after 3 months on the maximum dose of 5 mg/kg per day, CsA should be discontinued. For discontinuation, CsA should be gradually tapered while an alternative therapy is instituted, whenever possible, and not stopped ‘cold turkey.’ There are isolated cases of rebound in disease activity, including pustular flares, after withdrawal or discontinuation of CsA.10–13 For obese patients, the ideal body weight should be used to calculate the starting dosage of CsA.99 If clinical response is not adequate, then gradually increase the dosage, because calculation based on actual body weight is likely to result in an excessive dosage. Attention to this very important ideal body weight principle results in both substantially greater patient safety with CsA and substantial drug cost savings. The previously mentioned guidelines are consistent with the scientific data available and closely reflect the results of the 1996, 1998, and 2004 worldwide consensus conferences on CsA.14,86,87 It should be noted, however, that the FDA has recommended a maximum dermatologic dosage of 4 mg/kg daily to reflect adjustments from Sandimmune to Neoral based on bioavailability data, in which the overall ratio of bioavailability between these two drugs is about 5:4 respectively (see discussion in Pharmacology section). Q17.10 According to the FDA guidelines, CsA can be used continuously for up to 1 year. Continuous courses of CsA for up to 2 years may be used according to the worldwide consensus guidelines.86,87 Nevertheless, the authors feel that the optimal use of CsA is for a period of 3 to 4 months at a time as an acute agent to control a flare of psoriasis, or to eliminate or greatly improve generalized psoriasis. After 2 years of continuous, uninterrupted CsA use, one has to discontinue CsA to give the kidneys a ‘CsA holiday,’ per international guidelines. In this situation, there is no guideline on how long a patient needs to be off CsA before another course of CsA treatment can be restarted. Should individual patients (1) respond well to CsA, (2) be successfully tapered to a relatively low maintenance dose, and (3) have totally stable blood pressure, renal function, and other laboratory tests, continuous courses of CsA at least up to the above US guidelines, and perhaps to ‘worldwide’ guidelines, are reasonable. The authors recommend a ‘break’ of at least 12 weeks between courses of cyclosporine. Conversion from Sandimmune to Neoral or Gengraf Formulation. Q17.1 When converting patients from the original

CsA formulation (Sandimmune) to the microemulsion formulation (Neoral, Gengraf ), a 1:1 dose-conversion strategy is recommended. Patients who absorbed Sandimmune adequately are not likely to have increased absorption of CsA after being

196

PA RT I V

Systemic Immunomodulatory Drugs

Serum creatinine rises >30% above patient’s baseline

Repeat measurement within 2 weeks

Creatinine is sustained at >30% above patient’s baseline

Reduce CsA dose by at least 1 mg/kg per day (for at least 1 month)

Creatinine decreases to 30% above patient’s baseline

CsA treatment can be continued at new dosage

Stop CsA treatment

Creatinine returns to within 10% of patient’s baseline

CsA treatment can be resumed at lower dosage

• Fig. 17.3 Steps to follow with rising creatinine. CsA, Cyclosporine A. (Modified from Berth-Jones J, Voorhees JJ. Consensus conference on cyclosporin A microemulsion for psoriasis. Br J Dermatol. 1996;135(5):775–777.) 0 Cyclosporine dose (mg/kg per day)

PASI reduction (%)

–25

1.25

–50 2.5

–75 5.0 –100 0

1

2

3

4

6

8

12

Time (weeks)

• Fig. 17.4

Percentage of psoriasis area and severity index score reduction according to dose in the first 3 months of treatment with cyclosporine. (Modified from Timonen P, Friend D, Abeywickrama K, Laburte C, von Graffenried B, Feutren G. Efficacy of low-dose cyclosporin A in psoriasis; results of dosefinding studies. Br J Dermatol. 1990;122(Suppl 36):33–39.)

converted to Neoral. However, in patients who were relatively poor absorbers of Sandimmune, the absorption of CsA is likely to increase after being converted to Neoral. As a result, it may be necessary to make subsequent dose reduction in these patients to ensure that they are receiving the lowest effective dose. Gengraf is a trade name generic product considered bioequivalent to Neoral. Of note, the FDA approval for psoriasis therapy is for Neoral only, not Sandimmune.

Careful safety monitoring is mandatory after conversion. Blood pressure and serum creatinine should be measured before conversion, in addition to 2, 4, and 8 weeks thereafter. Hypertension or a significant increase in serum creatinine should be managed according to the guidelines above. Sequential Therapy Involving Cyclosporine and Acitretin.

The purpose of sequential therapy (Box 17.66,13,85,86,97) is to use medications in a deliberate sequence to optimize each drug’s

CHAPTER 17

Cyclosporine

197

Cyclosporine dose (mg/kg per day )

100

Cumulative remission rate (%)

5.0

75

2.5

50

1.25 25

0 0

1

2

3

4

6

8

12

Time (weeks)

• Fig. 17.5 Cumulative success rate in the first 3 months of treatment according to cyclosporine dose. (Modified from Timonen P, Friend D, Abeywickrama K, Laburte C, von Graffenried B, Feutren G. Efficacy of low-dose cyclosporin A in psoriasis; results of dose-finding studies. Br J Dermatol. 1990;122(Suppl 36):33–39.) • BOX 17.6 Rationale for Sequential Therapy for

Psoriasis • Some medications are more ideal for ‘quick fixes’ whereas others are more ideal for maintenance therapy • Systemic medications for psoriasis have both strengths and weaknesses for individual patients • Maximize the strength and minimize the weakness of each therapeutic agent involved • Sequential therapy involves three stages: • Stage 1—Clearing phase • Stage 2—Transitional phase • Stage 3—Maintenance phase • Sequential therapy with cyclosporine and acitretin can be a useful alternative to methotrexate therapy, although possible sequential therapy options include cyclosporine followed by methotrexate or a biologic agent.

strengths while minimizing each drug’s weaknesses.100 This is in contrast to the usual approach of treating psoriasis patients with one main therapeutic agent with the expectation of long-term use if it proves efficacious and switching agents if it does not work well. It is the authors’ experience that the sequential use of CsA and acitretin appears to be safe with close monitoring, considering their almost mutually exclusive AE profiles. In fact, the concurrent use of CsA and acitretin is common in transplant patients, who are at increased risk for developing skin cancer.101,102 Fig. 17.6 outlines an example of sequential use of CsA and acitretin. This sequence makes the best use of the strength of CsA as a ‘quick-fix’, rapidly acting agent that is well tolerated at high doses and typically induces complete clearance. Q17.11 Acitretin has a slow onset of action and dose-dependent AE such as hair loss and cheilitis at higher doses. Although a good

therapy for rapid clearance, CsA cannot be used for more than 1 to 2 years as a result of its AE profile. Thus, for patients with severe psoriasis it is logical to use CsA first to induce clearance, followed by acitretin for maintenance therapy. Used in sequence, CsA and acitretin are very effective in clearing severe psoriasis and safely maintaining long-term clearance. Sequential Therapy with Other Systemic Therapies.

The concurrent use of methotrexate and CsA in dermatology patients has not yet been determined to be safe. The concern is that reduction in renal function as a result of CsA, as demonstrated by an increase in serum creatinine, could cause a substantial reduction in methotrexate excretion. The net result may be an increased hematologic and hepatic risk from methotrexate. However, it is important to note that combination therapy with CsA and methotrexate has been proven safe in rheumatology patients,103 and is FDA approved for rheumatoid arthritis. The concurrent use of CsA and the biologic therapies for psoriasis also has not yet been determined to be safe, given that all the biologic therapies have at least some immunosuppressive qualities. However, sequential use of CsA transitioning to adalimumab (Humira), as published in a case series by the author (JK), appears to be a very good option.104

Summary Because of its tremendous efficacy and tolerability, CsA is a great addition to our therapeutic armamentarium in the treatment of psoriasis. To a degree, fear of AE, lack of specific knowledge about CsA, and misconceptions are prevalent among dermatologists in the United States regarding this agent. Given a proper understanding of the drug’s pharmacology and clinical use, its advantages and benefits can be made available to patients, especially for shortterm, effective control of severe psoriasis and, off-label, AD and PG patients. Despite the multiple biologic therapies now available

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PHASE 1

PHASE 2

PHASE 3

Clearing phase

Transition phase

Maintenance phase

PHASE 1

PHASE 2

PHASE 3A

PHASE 3B

Cyclosporine at maximum dermatologic dosage

Maintain cyclosporine at 4 mg/kg per day while introducing acitretin.later, taper off cyclosporine.

Maintain with acitretin

Maintain with acitretin and UVB or PUVA (Re-UVB or Re-PUVA)

• Fig. 17.6 An example of oral sequential therapy. PUVA, Psoralen and ultraviolet A; Re-PUVA, retinoid and PUVA; Re-UVB, retinoid and UVB; UVB, ultraviolet B.

to treat psoriasis, CsA tends to have one of the quickest onsets of action of all the systemic therapies, and therefore, may still be the ideal systemic agent for quickly controlling a severe psoriasis flare, including in patients who are flaring or rebounding while on a biologic therapy.

Acknowledgment The authors would like to acknowledge Dr. Chai Sue Lee for contributions to multiple previous editions of this chapter.

Bibliography: Important Reviews and Chapters General Overviews Amor KT, Ryan C, Menter A. The use of cyclosporine in dermatology: part I. J Am Acad Dermatol. 2010;63(6):925–946. Armstrong AW, Aldredge L, Yamauchi PS. managing patients with psoriasis in the busy clinic: practical tips for health care practitioners. J Cutan Med Surg. 2016;20(3):196–206. Gooderham M, Lynde CW, Papp K, et al. Review of systemic treatment options for adult atopic dermatitis. J Cutan Med Surg. 2017;21(1):31–39. Kaushik SB, Lebwohl MG. Psoriasis: which therapy for which patient: psoriasis comorbidities and preferred systemic agents. J Am Acad Dermatol. 2019;80(1):27–40. Kaushik SB, Lebwohl MG. Psoriasis: which therapy for which patient: focus on special populations and chronic infections. J Am Acad Dermatol. 2019;80(1):43–53. Ryan C, Amor KT, Menter A. The use of cyclosporine in dermatology: part II. J Am Acad Dermatol. 2010;63(6):949–972. Soleymani T, Vassantachart JM, Wu JJ. Comparison of guidelines for the use of cyclosporine for psoriasis: a critical appraisal and comprehensive review. J Drugs Dermatol. 2016;15(3):293–301. Consensus Statements Griffiths CE, Dubertret L, Ellis CN, et al. Cyclosporin in psoriasis clinical practice: an international consensus statement. Br J Dermatol. 2004;150(suppl 67):11–23. Lebwohl M, Ellis C, Gottlieb A, et  al. Cyclosporine consensus conference: with emphasis on the treatment of psoriasis. J Am Acad Dermatol. 1998;39(3):464–475. Rosmarin DM, Lebwohl M, Elewski BE, Gottlieb AB. Cyclosporine and psoriasis: 2008 national psoriasis foundation consensus conference. J Am Acad Dermatol. 2010;62(5):838–853.

Adverse Effects Overviews García-Bustínduy M, Escoda M, Guimerá FJ, et  al. Safety of longterm treatment with cyclosporin A in resistant chronic plaque psoriasis: a retrospective case series. J Eur Acad Dermatol Venereol. 2004;18(2):169–172. Markham T, Watson A, Rogers S. Adverse effects with long-term cyclosporin for severe psoriasis. Clin Exp Dermatol. 2002;27(2):111–114.

References* 2. Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Med. 1979;301(10):555. 3. Colombo D, Egan CG. Bioavailability of Sandimmun versus Sandimmun Neoral: a meta-analysis of published studies. Int J Immunopathol Pharamcol. 2010;23(4):1177–1183. 4. Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin and FK506. Immunol Today. 1992;13(4):136–142. 5. Heydendael VM, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med. 2003;349(7):658–665. 6. Timonen P, Friend D, Abeywickrama K, Laburte C, von Graffenried B, Feutren G. Efficacy of low-dose cyclosporin A in psoriasis; results of dosefinding studies. Br J Dermatol. 1990;122(suppl 36):33–39. 7. Feutren G, Friend D, Timonen P, Barnes A, Laburte C. Predictive value of cyclosporin A level for efficacy or renal dysfunction in psoriasis. Br J Dermatol. 1990;122(suppl 36):85–93. 14. Griffiths CE, Dubertret L, Ellis CN, et  al. Ciclosporin in psoriasis clinical practice: an international consensus statement. Br J Dermatol. 2004;150(suppl 67):11–23. 88. Lebwohl M, Ellis C, Gottlieb A, et  al. Cyclosporine consensus conference: with emphasis on the treatment of psoriasis. J Am Acad Dermatol. 1998;39(3):464–475. 96. Grossman RM, Chevret S, Abi-Rached J, Blanchet F, Dubertret L. Longterm safety of cyclosporine in the treatment of psoriasis. Arch Dermatol. 1996;132(6):623–629. 100. Paul C, Gallini A, Maza A, et  al. Evidence based recommendations on conventional systemic treatments in psoriasis: systematic review and expert opinion of a panel of dermatologists. J Eur Acad Dermatol Venereol. 2011;25(suppl 2):2–11. 101. Koo J. Systemic sequential therapy of psoriasis: a new paradigm for improved therapeutic results. J Am Acad Dermatol. 1999;41(3Pt2):S25–S28.

*Only a selection of references are printed here. All other references in the reference list are available online at www. expertconsult.com.

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41. Elgart G, Stover P, Larson K, et  al. Treatment of pyoderma gangrenosum with cyclosporine: results in seven patients. J Am Acad Dermatol. 1991;24(1):83–86. 42. Ormerod AD, Thomas KS, Craig FE, et al. Comparison of the two most commonly used treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial. BMJ. 2015;350:h2958. 43. Feldman SR, Lacy FA, Huang WW. The safety of treatments used in pyoderma gangrenosum. Expert Opin Drug Saf. 2018;17(1):55–61. 44. Farhi D, Wallach D. The neutrophilic dermatoses. Dermatol Nurs. 2008;20(4):274–276, 279–282. Atopic Dermatitis 45. Sowden JM, Berth-Jones J, Ross JS, et al. Double-blind, controlled, crossover study of cyclosporin in adult patients with severe refractory atopic dermatitis. Lancet. 1991;338(8760):137–140. 46. van Joost T, Heule F, Korstanje M, van den Broek MJ, Stenveld HJ, van Vloten WA. Cyclosporin in atopic dermatitis: a multicentre placebo-controlled study. Br J Dermatol. 1994;130(5):634–640. 47. Hernández-Martín A, Noguera-Morel L, Bernardino-Cuesta B, et  al. Cyclosporine A for severe atopic dermatitis in children. efficacy and safety in a retrospective study of 63 patients. J Eur Acad Dermatol Venereol. 2017;31(5):837–842. 48. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71(2):327–349. Alopecia 49. Shapiro J, Lui H, Tron V, Ho V. Systemic cyclosporine and low-dose prednisone in the treatment of chronic severe alopecia areata: a clinical and immunopathologic evaluation. J Am Acad Dermatol. 1997;36(1):114–117. 50. Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J. Alopecia areata update: part II. treatment. J Am Acad Dermatol. 2010;62(2):191–202. 51. Mirmirani P, Willey A, Price VH. Short course of oral cyclosporine lichen planopilaris. J Am Acad Dermatol. 2003;49(4): 667–671. Granulomatous Dermatoses 52. Fiallo P. Cyclosporin for the treatment of granuloma annulare. Br J Dermatol. 1998;138(2):369–370. 53. Filotico R, Vena GA, Coviello C, Angelini G. Cyclosporine in the treatment of generalized granuloma annulare. J Am Acad Dermatol. 1994;30(3):487–488. 54. Ho VC. Cyclosporine in the treatment of generalized granuloma annulare. J Am Acad Dermatol. 1995;32(2Pt1):298. 55. Gupta AK, Ellis CN, Nickoloff BJ, et al. Oral cyclosporine in the treatment of inflammatory and noninflammatory dermatoses. A clinical and immunopathologic analysis. Arch Dermatol. 1990;126(3):339–350. Disorders of Keratinization 56. Usuki K, Sekiyama M, Shimada T, Shimada S, Kanzaki T. Three cases of pityriasis rubra pilaris successfully treated with cyclosporin A Dermatology. 2000;200(4):324–327. 57. Wetzig T, Sticherling M. Juvenile pityriasis rubra pilaris: successful treatment with ciclosporin. Br J Dermatol. 2003;149(1):202–203. Photosensitivity Dermatoses 58. Stinco G, Codutti R, Frattasio A, De Francesco V, Patrone P. Chronic actinic dermatitis treated with cyclosporine-A. Eur J Dermatol. 2002;12(5):455–457.

Other Dermatoses 59. Herr H, Koh JK. Eosinophilic cellulitis (Wells’ syndrome) successfully treated with low-dose cyclosporine. J Korean Med Sci. 2001;16(5):664–668. 60. Kaneko K, Aoki M, Hattori S, Sato M, Kawana S. Successful treatment of Kimura’s disease with cyclosporine. J Am Acad Dermatol. 1999;41(5Pt2):893–894. 61. Peter RU, Ruzicka T, Eckert F. Low dose cyclosporine A in the treatment of disabling morphea. Arch Dermatol. 1991;127(9):1420–1421. 62. Berth-Jones J, Smith SG, Graham-Brown RA. Nodular prurigo responds to cyclosporin. Br J Dermatol. 1995;132(5):795–799. 63. Sommer S, Henderson CA. Papuloerythroderma of Ofuji responding to treatment with cyclosporin. Clin Exp Dermatol. 2000;25(4):293–295. 64. Avci O, Izler F, Pabuçcuoğlu U, Sahin T, Guneş AT. Effective treatment of persistent papular acantholytic dermatosis with cyclosporine. J Eur Acad Dermatol Venereol. 1998;11(2):162– 164. 65. Okada K, Ishikawa O, Miyachi Y. Purpura pigmentosa chronica successfully treated with oral cyclosporin A. Br J Dermatol. 1996;134(1):180–181. 66. Kiyohara A, Takamori K, Nizuma N, Ogawa H. Successful treatment of severe recurrent Reiter’s syndrome with cyclosporine. J Am Acad Dermatol. 1997;36(3Pt1):482–483. 67. Bata-Csorgo Z, Husz S, Foldes M, et al. Scleromyxedema. J Am Acad Dermatol. 1999;41(2Pt2):343–346. 68. Zimmermann S, Sekula P, Venhoff M, et al. Systemic immunomodulating therapies for Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol. 2017;153(6):514–522. 69. González-Herrada C, Rodríguez-Martín S, Cachafeiro L, et al. Cyclosporine use in epidermal necrolysis is associated with an important mortality reduction: evidence from three different approaches. J Invest Dermatol. 2017;137(10):2092–2100. 70. Ottawa Hospital Research Institute. Cyclosporine and etanercept in Stevens-Johnson syndrome and toxic epidermal necrolysis (NATIENS). https://clinicaltrials.gov/ct2/show/ NCT02987257. NLM identifier: NCT02987257. Accessed February 6, 2019. Urticaria 71. Toubi E, Blant A, Kessel A, Golan TD. Low-dose cyclosporin A in the treatment of severe chronic idiopathic urticaria. Allergy. 1997;52(3):312–316. 72. Grattan CE, O’Donnell BF, Francis DM, et  al. Randomized double-blind study of cyclosporin in chronic ‘idiopathic’ urticaria. Br J Dermatol. 2000;143(2):365–372. 73. Fradin MS, Ellis CN, Goldfarb MT, Voorhees JJ. Oral cyclosporine for severe chronic idiopathic urticaria and angioedema. J Am Acad Dermatol. 1991;25(6Pt1):1065–1067. 74. Boubouka CD, Charissi C, Kouimintzis D, Kalogeromitros D, Stavropoulos PG, Katsarou A. Treatment of autoimmune urticaria with low-dose cyclosporin A: a one-year follow-up. Acta Derm Venereol. 2011;91(1):50–54. 75. Serhat Inaloz H, Ozturk S, Akcali C, Kirtak N, Tarakcioglu M. Low-dose and short-term cyclosporine treatment in patients with chronic idiopathic urticaria: a clinical and immunological evaluation. J Dermatol. 2008;35(5):276–282. 76. Marsland AM, Beck MH. Cold urticaria responding to systemic ciclosporin. Br J Dermatol. 2003;149(1):193–227. 77. Edström DW, Ros AM. Cyclosporin A therapy for severe solar urticaria. Photodermatol Photoimmunol Photomed. 1997;13(1– 2):61–63.

References

Psoriasis 78. Rosenbach M, Hsu S, Korman NJ, et al. Treatment of erythrodermic psoriasis: from the medical board of the national psoriasis foundation. J Am Acad Dermatol. 2010;62(4):655–662. 79. Di Lernia V, Grenzi L, Guareschi E, Ricci C. Rapid clearing of acute generalized exanthematous pustulosis after administering of cyclosporine. Clin Exp Dermatol. 2009;34(8):e757–e759. Atopic dermatitis 80. Otsuka A, Tanioka M, Nakagawa Y, et al. Effects of cyclosporine on pruritus and serum IL-31 levels in patients with atopic dermatitis. Eur J Dermatol. 2011;21(5):816–817. 81. Haw S, Shin MK, Haw CR. The efficacy and safety of longterm oral cyclosporine treatment for patients with atopic dermatitis. Ann Dermatol. 2010;22(1):9–15. 82. Totri CR, Eichenfield LF, Logan K, et al. Prescribing practices for systemic agents in the treatment of severe pediatric atopic dermatitis in the US and Canada: the PeDRA TREAT survey. J Am Acad Dermatol. 2017;76(2):281–285. Contraindications 83. Zackheim HS, Koo J, LeBoit PE, et  al. Psoriasiform mycosis fungoides with fatal outcome after treatment with cyclosporine. J Am Acad Dermatol. 2002;47(1):155–157. 84. Maza A, Montaudié H, Sbidian E, et  al. Oral cyclosporin in psoriasis: a systematic review on treatment modalities, risk of kidney toxicity and evidence for use in non-plaque psoriasis. J Eur Acad Dermatol Venereol. 2011;25(suppl 2):19–27. Adverse Effects—Renal and Hypertension 85. Zachariae H, Hansen HE, Kragballe K, Olsen S. Morphologic renal changes during cyclosporine treatment of psoriasis. J Am Acad Dermatol. 1992;26(3Pt2):415–419. 86. Berth-Jones J, Voorhees JJ. Consensus conference on cyclosporin a microemulsion for psoriasis, June 1996. Br J Dermatol. 1996;135(5):775–777. 87. Lebwohl M, Ellis C, Gottlieb A, et al. Cyclosporine consensus conference: with emphasis on the treatment of psoriasis. J Am Acad Dermatol. 1998;39(3):464–475. 88. Luke RG. Mechanism of cyclosporine-induced hypertension. Am J Hypertens. 1991;4(5Pt1):468–471. 89. Novartis Pharmaceuticals. Neoral prescribing information; 2015. https://www.pharma.us.novartis.com/sites/www.pharma. us.novartis.com/files/neoral.pdf. Accessed February 6, 2019. Malignancy Risk 90. Paul C, Ho VC, McGeown C, et  al. Risk of malignancies in psoriasis treated with cyclosporine: a 5-yr cohort study. J Invest Dermatol. 2003;120(2):211–216. 91. Muellenhoff MW, Koo JY. Cyclosporine and skin cancer: an international dermatologic perspective over 25 years of

92.

93.

94. 95. 96. 97.

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experience. A comprehensive review and pursuit to define safe use of cyclosporine in dermatology. J Dermatolog Treat. 2012;23(4):290–304. Lamarque V, Monka C, Commare MC, et  al. Risk of malignancies in patients treated with Sandimmum for autoimmune diseases. In: Touraine JL, Traeger J, Betuel H, eds. Cancer in Transplantation: Prevention and Treatment. Dordrecht: Kluwer Academic; 1996:141–148. Koo J, Kadonaga JN, Wintroub BV, Lozada-Nur FI. The development of B-cell lymphoma in a patient with psoriasis treated with cyclosporine. J Am Acad Dermatol. 1992;26(5Pt2): 836–840. Krupp P, Monka C. Side-effect profile of cyclosporin A in patients treated for psoriasis. Br J Dermatol. 1990;122(suppl 36):47–56. Grossman RM, Chevret S, Abi-Rached J, Blanchet F, Dubertret L. Long-term safety of cyclosporine in the treatment of psoriasis. Arch Dermatol. 1996;132(6):623–629. Cliff S, Pettengell R, Gharge S, Marsden RA. B-cell lymphoma developing in a patient on cyclosporin for recalcitrant psoriasis. Br J Dermatol. 1999;140(4):763–765. Corazza M, Zampino MR, Montanari A, Altieri E, Virgili A. Primary cutaneous CD30+ large T-cell lymphoma in a patient with psoriasis treated with cyclosporine. Dermatology. 2003;206(4):330–333.

Miscellaneous Issues 98. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80(6):565–581. 99. Paul C, Gallini A, Maza A, et  al. Evidence based recommendations on conventional systemic treatments in psoriasis: systematic review and expert opinion of a panel of dermatologists. J Eur Acad Dermatol Venereol. 2011;25(suppl 2):2–11. 100. Koo J. Systemic sequential therapy of psoriasis: a new paradigm for improved therapeutic results. J Am Acad Dermatol. 1999;41(3Pt2):S25–S28. 101. Bavinck JNB, Tieben LM, Van der Woude FJ, et  al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol. 1995;13(8): 1933–1938. 102. Yuan ZF, Davis A, Macdonald K, Bailey RR. Use of acitretin for the skin complications in renal transplant recipients. N Z Med J. 1995;108(1002):255–256. 103. Klein A, Vogt T, Wenzel SM, Fleck M, Landthaler M. Cyclosporin combined with methotrexate in two patients with recalcitrant subacute cutaneous lupus erythematosus. Australas J Dermatol. 2011;52(1):43–47. 104. Gattu S, Wu JJ, Koo JY. Can adalimumab make a smooth and easy transition from cyclosporine a reality? A case series of successful transitions. Psoriasis Forum, Winter 2009;15(2):33–35.

18 Phosphodiesterase-4 and Janus Kinase Inhibitors GILLIAN WESTON AND BRUCE STROBER

QUESTIONS Q18.1 What are the most important differences between small molecule drugs (such as apremilast and tofacitinib) and biologics? (Pg. 200)

Q18.6 What is the role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in inflammatory dermatoses? (Pg. 203)

Q18.2 What is the role of phosphodiesterase 4 in inflammatory diseases? (Pg. 200 )

Q18.7 What drugs inhibit the JAK/STAT pathway and for what diseases are these drugs used? (Pg. 203x6)

Q18.3 What drugs inhibit phosphodiesterase 4 and for what diseases are these drugs being used for? (Pgs. 200, 201, 202)

Q18.8 What are the Boxed Warnings in the prescribing information for tofacitinib? (Pgs. 204, 205x2)

Q18.4 What can be expected of apremilast in terms of efficacy for psoriasis and psoriatic arthritis, based on clinical trial results? (Pg. 201x2 )

Q18.9 What laboratory monitoring is recommended for patients taking tofacitinib? (Pg. 206x3)

Q18.5 What is the most common adverse effect experienced by patients on apremilast? (Pgs. 201, 202)

Q18.10 What other drugs targeting the JAK/STAT pathway are currently in development? (Pg. 207x3)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R AE Adverse events ACR American College of Rheumatology ANC Absolute neutrophil count ATP Adenosine triphosphate BD Behçet disease BSA Body surface area cAMP Cyclic adenosine monophosphate CBC Complete blood count DMARD Disease-modifying antirheumatic drugs EASI Eczema Area and Severity Index FDA US Food and Drug Administration GI Gastrointestinal HBV Hepatitis B virus IFN-γ Interferon-gamma IL Interleukin

ISGA Investigators Static Global Assessment JAK Janus kinase MACE Major adverse cardiovascular events NAPSI Nail Psoriasis Severity Index NSAID(s) Nonsteroidal anti-inflammatory drug(s) PASI Psoriasis Area and Severity Index PDE4 Phosphodiesterase 4 PGA Physicians Global Assessment PKA Protein kinase A PPPGA Palmoplantar Psoriasis Physician Global Assessment SALT Severity of Alopecia Tool SAPHO Synovitis, acne, pustulosis, hyperostosis, osteitis ScPGA Scalp Physicians Global Assessment STAT Signal transducer activator transcription TNF-α Tumor necrosis factor-alpha

Introduction

administered either topically or orally have also been recently developed. New targets of small molecule drugs include phosphodiesterase 4 (PDE4) and the Janus kinase (JAK) family of nonreceptor tyrosine kinases. These approaches show promise in treating various inflammatory cutaneous conditions, including atopic dermatitis (AD), psoriasis, alopecia areata, and vitiligo.

Since 2000, we have witnessed a large number of approved immunomodulatory therapies for inflammatory diseases. Many of these are biologic medications: injectable or infusable large, high molecular weight proteins. However, a variety of small molecule drugs

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the plasma membrane.2 Once synthesized, cAMP can activate a multitude of signaling molecules that mediate downstream activities.3 Specifically, in immune cells, high levels of cAMP activate the protein kinase A (PKA) pathway, which results in the suppressed expression of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-17 (IL-17) and interferon-gamma (IFN-γ) and, concomitantly, the production of antiinflammatory mediators, such as interleukin-10 (IL-10).4,5 These effects are inhibited by PDE4, the predominant cAMP-degrading enzyme in inflammatory cells.6 Effects of PDE4 and the mechanism of action of apremilast are depicted in Fig. 18.1.

Small Molecule Treatments Q18.1 Small molecule drugs are not new; in fact, they make up over 90% of drugs currently prescribed.1 Their small size allows them to be readily absorbed into the bloodstream after oral or topical administration and subsequently reach many different tissues in the body. At the target cell, unlike larger biologic drugs, these molecules can also easily penetrate the cell membrane to interact with intracellular proteins.

Mechanism of Action of Phosphodiesterase 4 Inhibition

Phosphodiesterase 4 Inhibitor Therapy Q18.3 There are several PDE4 inhibitors approved for the treatment of multiple diseases, including depression, chronic obstructive pulmonary disease, psoriasis and AD. When PDE4 is inhibited, cAMP cannot be degraded. Therefore high levels of cAMP are permitted to exert downstream anti-inflammatory effects, via the PKA pathway.7

Q18.2 Cyclic adenosine monophosphate (cAMP) was the first identified second messenger of extracellular ligand signals and is a key regulator in an array of cellular actions necessary for the function of nearly every system in the body, with the immune system as no exception.2 cAMP is synthesized from adenosine triphosphate (ATP) by adenylate cyclase, an enzyme anchored intracellularly on

Pro-inflammatory cytokines TNF-α IFN-γ

cAMP

IL-17

AMP

PDE 4 AMP

AMP

IL-10

Anti-inflammatory cytokines Inflammatory cell Pro-inflammatory cytokines IL-10

cAMP

AMP

PDE 4 AMP

TNF-α

AMP

IFN-γ

Apremilast

Anti-inflammatory cytokines

Inflammatory cell

• Fig. 18.1

IL-17

Mechanism of action of apremilast. In inflammatory cells, cyclic adenosine monophosphate (cAMP) is converted to adenosine monophosphate (AMP) via phosphodiesterase 4 (PDE4). Increased level of AMP lead to release of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-23 and IL-17 and decreased expression of anti-inflammatory cytokines, such as IL-10. Apremilast inhibits the action of PDE4, which increases levels of cAMP, decreases levels of AMP and which translates to a more anti-inflammatory downstream cytokine profile (increased anti-inflammatory cytokines and decreased proinflammatory cytokines.

CHAPTER 18

Apremilast Clinical Use US Food and Drug Administration-Approved Indications Psoriasis. Q18.3 Apremilast was approved by the US Food

and Drug Administration (FDA) initially in March 2014 for treatment of active psoriatic arthritis. Several months later in September 2014, its approved indications expanded to include patients with moderate to severe plaque psoriasis for whom phototherapy or other systemic therapy is appropriate. Subset analyses within its phase 3 registrational studies demonstrate efficacy in specifically treating scalp and nail psoriasis, as well as palmoplantar psoriasis associated with moderate-to-severe plaque psoriasis affecting large areas of the rest of the body.8,9 Apremilast is available as 30 mg tablets and as 10 mg, 20 mg, and 30 mg tablets in a titration pack used at the beginning of therapy and that might reduce gastrointestinal (GI) adverse effects (AE). Patients can take apremilast with or without food, but should not alter the tablet in any way including crushing, splitting, or chewing.10 Patients with creatinine clearance of less than 30 mL/min should only take apremilast 30 mg daily.10 No dose adjustment is necessary for geriatric patients or those with hepatic impairment.10 No laboratory monitoring is required for patients on apremilast therapy.10 Q18.4 In patients with moderate to severe plaque psoriasis, Psoriasis Area and Severity Index (PASI)-75 was achieved in 28.8% to 39.8% of patients receiving apremilast compared with 5.3% to 11% in patients receiving placebo after 16 weeks of therapy.11–13 Patients, taking apremilast in general, have reported improvements in quality of life measures when compared with patients in matched placebo groups.14,15 After 16 weeks of apremilast therapy, psoriasis patients with nail involvement had 22.5% to 29.0% improvement in the Nail Psoriasis Severity Index (NAPSI) score, compared with 6.5% to 7.1% improvement seen for the placebo population.8 Further, 40.9% to 46.5% of patients with severe scalp psoriasis who took apremilast 30 mg twice daily achieved a Scalp Physicians Global Assessment (ScPGA) of minimal or clear after 16 weeks.8 Significant improvements in palmoplantar psoriasis were also noted after 16 weeks of apremilast therapy; 46% of patients with a palmoplantar psoriasis physician global assessment (PPPGA) score of 1 or greater, indicating active disease at baseline achieved a PPPGA score of 0 (clear) compared with 25% of patients receiving placebo.9 It should be noted that this was a secondary analysis of patients in the phase III study of moderate-to-severe psoriasis, and that these patients did not have palmoplantar psoriasis as the primary feature of their disease. A separate study of patients with palmoplantar psoriasis as their primary disease failed to reach statistical significance at its primary endpoint.16 Psoriatic Arthritis. Q18.4 In a study of psoriatic arthritis patients, 32.1% to 38.1% of patients on apremilast 30 mg twice daily achieved American College of Rheumatology (ACR)-20 compared with 18.9% to 19.0% of patients receiving placebo.17,18 At 52 weeks, an as observed statistical analysis showed that ACR20 was achieved in 54.6% patients receiving the same dosing.17,18 Off-Label Uses for Apremilast. Although not FDA approved for Behçet disease (BD), randomized clinical trials have shown that BD patients, receiving apremilast, had reduction in the number of oral ulcers, genital ulcers, reduction in pain from oral ulcers and improvement in quality of life measures at 12 weeks.19 In addition, small pilot studies have showed that apremilast may be

Phosphodiesterase-4 and Janus Kinase Inhibitors

201

of benefit in patients with discoid lupus erythematosus and lichen planus.20,21 Recent clinical studies have also shown that more patients with active ulcerative colitis, who receive apremilast, reach clinical remission within 12 weeks than do patients receiving placebo.22 Individual reports of apremilast efficacy in treating various other disease states have been published as well; these include pityriasis rubra pilaris, vitiligo and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome.23–25 Apremilast is also being studied for efficacy and safety in many other dermatologic conditions, including frontal fibrosing alopecia, chronic itch, nummular eczema, hidradenitis suppurativa, AD, contact dermatitis, severe acne, alopecia areata, rosacea, prurigo nodularis, cutaneous sarcoidosis, and vulvodynia. The true efficacy of apremilast in treating these conditions is left to be determined. Indications for apremilast are summarized in Box 18.1. Pharmacology and Pharmacokinetics.

Apremilast is metabolized in the liver, primarily by cytochrome P-450 (CYP)3A4, but also by CYP1A1 and CYP2A6. Coadministration with potent CYP inducers, including rifampin, phenobarbital, carbamazepine, and phenytoin should be avoided because it may result in decreased apremilast drug levels.10 A summary of drug interactions that should be considered when prescribing apremilast can be found in Table 18.1. The apremilast half-life is approximately 6 to 9 hours, necessitating apremilast as twice daily dosing. The drug is excreted primarily through the urine, but a small portion is excreted through the feces.10 Contraindications and Adverse Effects. Allergy to apremilast or to any of the ingredients in the formulation is the only absolute contraindication to its use.10 It has not been studied in pregnant or lactating patients or pediatric populations and, therefore risk in these scenarios cannot be ruled out.10 Gastrointestinal Effects. Q18.5 The most common AE, occurring in up to 19% of patients, are GI in nature and include diarrhea, nausea and vomiting, and tend to occur during the first few weeks of therapy.11,18 The risk of GI AE may be increased in elderly patients and those that use certain medications, such as those that can cause volume loss and dehydration or hypotension. GI AE may be minimized with use of the titration starter pack.10 Other Adverse Effects. Other AE occurring in greater than 5% of patients include upper respiratory tract infection, rhinorrhea, • BOX 18.1 Apremilast Indications10,19–25 US Food and Drug Administration-Approved Indications Psoriasis Psoriatic arthritis

Off-Label Dermatologic Uses Neutrophilic Dermatoses Behçet disease SAPHO syndrome

Autoimmune Connective Tissue Diseases Discoid lupus erythematosus

Papulosquamous Dermatoses Lichen planus Pityriasis rubra pilaris

Pigmentary Disorders Vitiligo SAPHO, Synovitis, acne, pustulosis, hyperostosis, and osteitis.

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TABLE Drug Interactions—Apremilast 18.1

Drug Category

Drug Examples

Comments

Anticonvulsants

Phenytoin, carbamazepine, others

Strong CYP3A4 inducers; may lower levels of apremilast with loss efficacy, but no major adverse effects

Rifamycins

Rifampin, rifabutin

Strong CYP3A4 inducers: lower levels of apremilast with loss of efficacy, but no major adverse effects

Braf inhibitors

Dabrafenib

May increase serum concentrations of apremilast

---

---

Note—Apremilast is a CYP 3A4 substrate; however, primary source lists no major interactions with CYP3A4 inhibitors … would be “cautious” with strong inhibitors, such as selected azoles, macrolides

Biologics

Tocilizumab

Minor reduction apremilast serum concentrations

Supplements

St. John’s wort

Strong CYP3A4 inducers: lower levels of apremilast with loss of efficacy, but no major adverse effects

Relatively High-Risk Drug

Interactionsa

Lower-Risk Drug Interactions

aOverall highest-risk drug interactions indicated in bold italics (none for apremilast). The dramatic increase in number of drug interactions in medicine requires some degree of selectivity in these tables (common usage, relative risk, focus on outpatient rx). CYP, Cytochrome P-450.

Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. (http://www.hanstenandhorn.com/).

sneezing, congestion, abdominal pain, tension headache, and headache.11,18 Some apremilast patients experience weight loss; 10% to 12% of patients might lose 5% to 10% of baseline body weight, whereas more than10% body weight loss occurs in 2% of patients.10 Depression and Suicide Risk. Q18.5 In clinical studies, some patients taking apremilast reported depression or suicidal behavior. In psoriasis studies, 1.3% of patients on apremilast reported depression compared with 0.4% in the placebo group.10 Similar rates were reported in studies in patients with psoriatic arthritis.10 Suicidal behavior was also observed in both apremilast and placebo groups in studies of both psoriasis and psoriatic arthritis. However, rates of suicide attempts were higher in the placebo groups (one patient on apremilast, three patients on placebo).10 The risks and benefits of treatment with apremilast should we weighed carefully in each patient, especially those with a history of depression, and patients should be monitored for depression, suicidal thoughts, or other mood changes while on apremilast therapy. Contraindications and potentially serious AE associated with apremilast are summarized in Box 18.2.

• BOX 18.2 Drug Risks Profile—Apremilast10,11,18 Contraindications Hypersensitivity to apremilast or components formulation

Boxed Warnings None listed

Warnings & Precautionsa Gastrointestinal (GI)

Psychiatric

aSevere

aUse

nausea, vomiting, diarrhea reported, especially first few weeks of therapy May cause weight loss; monitor regularly

with caution in patients with prior depression, suicidal ideation/behavior

Renal Caution with creatinine clearance > clarithromycin > azithromycin

CYP3A4 inhibitors which ↑ retinoids drug levels and resultant toxicity—lipids, liver toxicity, etc.; given that systemic retinoids do not have a narrow therapeutic index, thus more moderate risk vs. CsA

Calcineurin inhibitors

Cyclosporine

When used in combination with acitretin → result in CsA ↑ levels with resultant toxicity

Folate antagonists

Methotrexate

When used in conjunction with long-term acitretin moderate potential for liver toxicity

Habits

Alcohol

Significant alcohol consumption may lead to re-esterification of acitretin to etretinate (long half-life)

Vitamins

Vitamin A supplements

Potential for symptoms of hypervitaminosis A; conceptually ↑ typical adverse effects of isotretinoin

Rifamycin antibacterials

Rifampin, rifabutin, rifapentine

CYP3A4 induction with resultant ↓ retinoid drug levels and loss efficacy; this effect takes 1–2 weeks

Aromatic anticonvulsants

Phenytoin, carbamazepine, oxcarbazepine, phenobarbital

same (oxcarbazepine weak CYP3A4 inducer)

Antifungals

Griseofulvin

same

Hormonal contraceptives

Progesterone only, combined oral contraceptives

May ↓ efficacy of hormonal contraception when used in combination with retinoids (controversial); the possibility at least supports the need for two methods of contraception

Lower-Risk Drug Interactions

aOverall

highest-risk drug interactions indicated in bold italics. CsA, Cyclosporine, CYP, Cytochrome P-450.

The dramatic increase in number of drug interactions in medicine requires some degree of selectivity in these tables (common usage, relative risk, focus on outpatient rx). Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. (http://www.hanstenandhorn.com/).

or discontinuation. The incidence of leukopenia and other hematologic abnormalities is much less frequent with first- and secondgeneration retinoids.103

Drug Interactions Formal studies of drug interactions with retinoids have been limited. Table 22.4 lists both well-documented interactions and interactions that can be anticipated based on the CYP3A4 metabolism of retinoids.

Monitoring Guidelines For monitoring guidelines see Boxes 22.8 and 22.9. Most urine pregnancy tests have a threshold detection limit of 20 to 50 mIU/mL. The serum pregnancy tests are more sensitive and have a better threshold detection limit of 1 to 5 mIU/mL. Urinary concentrations of β-human chorionic gonadotropin (βHCG) vary with the patient’s physiology, state of hydration, and urine volume. Because of these factors, the urine pregnancy test may not be sensitive enough until 6 to 8 days after conception, when the β-HCG level approaches 30 mIU/mL. If the urine pregnancy test is used, the first void of the day should be collected.

In general, implantable, injectable, and oral birth control hormones are most effective (Box 22.5). Diaphragm, spermicide, and condom, when used together, can be highly effective. Other than abstinence, no method of birth control is completely reliable. Women with a history of infertility should use contraceptives, and women who have undergone tubal ligation should ideally use a second form of contraception.

Therapeutic Guidelines Q22.12 Box 22.10 contains a therapeutic guidelines checklist for retinoid therapy. Two key issues influence the decision-making process regarding the selection of appropriate retinoids for therapy. First, retinoids are the single most effective category of drugs available for acne vulgaris and many disorders of keratinization and are strong contenders for therapy in severe presentations of dermatoses, such as psoriasis, pityriasis rubra pilaris, and mycosis fungoides. Second, major systemic AE, such as teratogenicity and ocular, bone, lipid, and liver AE make careful patient selection and ongoing laboratory surveillance critical. Even after thoroughly addressing the items in Box 22.10, there are still significant potential risks with synthetic retinoid therapy. Only physicians thoroughly familiar with the risks, monitoring guidelines, and elements of patient education should prescribe the systemic

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Systemic Retinoids

259

• BOX 22.8 Isotretinoin and Acitretin Monitoring Guidelines Baseline

Laboratorya,d

Examination

Monthly for the first 3–6 months, then every 3 months • Complete blood count (CBC) with plateletb • Liver function tests (AST, ALT) • Fasting lipid studiesc (triglycerides, cholesterol–order LDL and HDL cholesterol periodically) • Renal function testse (optional urinalysis) • Serum or urine pregnancy test monthly for women of childbearing potential (and at end of therapy)

• C areful history and physical examination • Identify those patients at increased risk for toxicity or adverse effects • Document concomitant medications that may interact with retinoids (see Table 22.4)

Laboratorya S erum or urine pregnancy testb (in women of childbearing potential) Complete blood count (CBC) with platelets Liver function tests (AST, ALT, alkaline phosphatase, bilirubin) Lipid profile during fastingc (triglycerides, total cholesterol, LDL and HDL cholesterol) • Renal function tests (blood urea nitrogen, creatinine) • Optional urinalysis (if patients have renal disease, proteinuria, diabetes or hypertension) • • • •

Special Tests • C onsider baseline x-rays of wrists, ankles or thoracic spine if plan longterm retinoid therapy • Consider ophthalmologic examination if patients have a history of cataracts or retinopathy

Follow-Up Examination Clinical evaluation monthly for first 3–6 months, then every 3 months • Assessment of patient response, improvement, and complaints of adverse effects • Routine physical examination of lesional skin • Additional/focused physical examination of any reported adverse effects

Special Tests Periodically as indicated by symptoms • Consider yearly x-rays of wrists, ankles or thoracic spine with long-term retinoid therapy • Radiographic studies of significantly symptomatic joints with long-term therapy • Complete ophthalmologic examination if patients report visual changes (see text for components) aMore

frequent surveillance is needed if laboratory parameters are abnormal or with high-risk patients bGuidelines require two pregnancy tests before isotretinoin therapy. Isotretinoin therapy should be initiated on the second day of next normal menstrual cycle or 11 or more days after last unprotected intercourse cCheck lipids after a 12 hours fast and 36 hour or longer abstinence from ethanol dWhen isotretinoin is used for a 20 week acne course, it is reasonable to discontinue monitoring (other than pregnancy testing) after 8-12 weeks if laboratory results have been normal and the dose is constant in asymptomatic patients eRenal function and hematologic tests are infrequently altered by retinoids. Consider ordering these tests every other time laboratory testing is done ALT, Alanine transaminase; AST, aspartate transaminase, HDL, high density lipoprotein; LDH, lactate dehydrogenase.

• BOX 22.9 Bexarotene Monitoring Guidelines Baseline Examination • C areful history and physical examination • Identify those patients at increased risk for toxicity or adverse effects: liver disease or cirrhosis, biliary tract disease, excessive alcohol consumption, prior pancreatitis, thyroid disease, uncontrolled hyperlipidemia, uncontrolled diabetes mellitus, HIV, leukopenia, chronic infection, cataracts • Document concomitant medications that may interact with retinoids (see Table 22.4)

Laboratorya • • • •

S erum pregnancy test (in women of childbearing potential) Complete blood count (CBC) with platelets and differential count Liver function tests (AST, ALT, alkaline phosphatase, bilirubin) Lipid profile during fastingb(triglycerides, total cholesterol, LDL and HDL cholesterol) • Renal function tests (blood urea nitrogen, creatinine) • Thyroid function tests: TSH, T4 • Optional urinalysis (if patients have renal diseases, proteinuria, diabetes or hypertension)

Special Tests • B aseline ophthalmologic examination if patients have a history of cataracts

Follow-Up Examination Clinical evaluation every 2 weeks for first 4–8 weeks, then monthly for the next 3 months; long-term clinical evaluation every 2–3 months

• Assessment of patient clinical response and for adverse side effects • Additional/focused physical examination of any reported side effects

Laboratory Every 1–2 weeks until the lipid response to Targretin is established (usually 2–4 wks), then as subsequently • Lipid profile during fastingb (triglycerides, total cholesterol, LDL and HDL cholesterol) Monthly for the first 3–6 months, then every 3 months • Complete blood count (CBC) with platelets and differential count • Liver function tests (AST, ALT); if elevated can also order bilirubin, alkaline phosphatase • Renal function testsc (optional urinalysis) • Serum or urine pregnancy test for women of childbearing potential (continue monthly indefinitely) • Thyroid function tests: TSH (at least), possibly T4 as well (reasonable to follow-up just 1–2 times)

Special Tests • R epeat ophthalmologic examination periodically during treatment if patients have a history of abnormal ocular findings before retinoid therapy aMore

frequent surveillance is needed if laboratory parameters are abnormal or with high-risk patients bCheck lipids after a 12 hours fast and 36 hour or longer abstinence from ethanol cRenal function tests and urinalysis are infrequently altered by bexarotene. Consider ordering these tests every other time laboratory testing is done ALT, Alanine transaminase; AST, aspartate transaminase, HDL, high density lipoprotein; HIV, human immunodeficiency virus; LDH, lactate dehydrogenase, TSH, thyroid stimulating hormone; T4, thyroxine.

260

PA RT I V

Systemic Immunomodulatory Drugs

• BOX 22.10 Therapeutic Guidelines Checklist Risk–benefit analysis is best performed when considering the following issues • P atient age and gender—use particular caution for children and for women of childbearing potential. • D isease responsiveness—the most appropriate retinoid drug choice, dose, and duration of therapy needs to be chosen; whether a sustained remission of the disease being treated is possible is of importance. • D isease severity—systemic retinoids are best used for conditions that are severe, involve large body surface areas (over 10%), and/or a significantly disabling on a physical or an emotional basis. • P rior alternative therapies—it is important to consider other topical and systemic therapies; systemic retinoids may be the treatment of choice if other treatment options are impractical, too costly, induce important adverse effects, or have worrisome drug interactions. • A djunctive therapy—when possible, use systemic retinoids in combination with other topical or systemic therapies to enhance efficacy and/or reduce adverse effects. • R otational or sequential therapy—using psoriasis as an example, longterm adverse effects may be minimized by alternating between retinoids and other therapeutic options, such as methotrexate, cyclosporine, PUVA or UVB phototherapy, in addition to newer biologic therapy options. Additional issues to address to optimize systemic retinoid therapy safety • D ose and duration—a patient should take the lowest possible retinoid dose for the briefest possible duration that will be therapeutically beneficial; upon adequate disease control, the dose can be tapered completely or more ideally reduced to the lowest effective maintenance dose to sustain disease control. • L aboratory surveillance—this should be done as outline in the Monitoring Guidelines boxes.

retinoids, especially bexarotene. Properly monitored, some of the most gratifying clinical results in dermatology can be obtained through the appropriate use of systemic retinoids.

Acknowledgment The Editors would like to thank Matthew J. Zirwas for his contribution to the second edition of this chapter.

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• P atient education—this education should particularly emphasize lipid, hepatic, teratogenic, psychiatric, and musculoskeletal adverse effects. • M anagement of adverse effects—maximum patient compliance require patient efforts directed at minimizing mucocutaneous adverse effects and awareness of expected minor hair, nail, and systemic adverse effects. Female patients should avoid pregnancy at all costs when using systemic retinoid therapy. In addition ‘new’ guidelines with the iPledge system, the following guidelines are useful reminders: • P atient selection—the patient’s capacity to understand the risk of serious teratogenicity and the importance of complete compliance with pregnancy prevention measures is a critical determinant in retinoid therapy decision. • P atient education—optimal patient education involves both the physician’s careful explanation and information handouts that address the important issues regarding teratogenicity. After the patient has heard and read these instructions, it is important to provide the patient adequate opportunity to ask any questions she may have. Mandatory participation in the iPledge program (see Box 22.6) provides an ongoing reminder of the teratogenicity potential. • I nformed consent documentation—for isotretinoin the iPledge system is adequate from a medicolegal perspective; thorough chart documentation of the earlier discussion is important. • C ontraception and Exclusion of pregnancy—see Box 22.5. • A nticipating options—the female patient should consider available options if pregnancy occurs before initiating retinoid therapy; it is helpful to document her thoughts on this subject in the medical record. PUVA, Psoralen and ultraviolet A; UVB, ultraviolet B.

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144. Lambert RW, Smith RE. Effects of 13-cis-retinoic acid on the hamster meibomian gland. J Invest Dermatol. 1989;92(3):321– 325. 145. Gross EG, Helfgott MA. Retinoids and the eye. Dermatol Clin. 1992;10(3):521–531. 146. Weleber RG, Denman ST, Hanifin JM, Cunningham WJ. Abnormal retinal function associated with isotretinoin therapy for acne. Arch Ophthalmol. 1986;104(6):831–837. 147. Sieving PA, Chaudhry P, Kondo M, et al. Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc Natl Acad Sci U S A. 2001;98(4):1835–1840. 148. Egger SF, Huber-Spitzy V, Böhler K, et al. Ocular side effects associated with 13-cis-retinoic acid therapy for acne vulgaris: clinical features, alterations of tearfilm and conjunctival flora. Acta Ophthalmol Scand. 1995;73(4):355–357. 149. Ellis CN, Krach KJ. Uses and complications of isotretinoin therapy. J Am Acad Dermatol. 2001;45(5):S150–S157. 150. Roenigk HH, Callen JP, Guzzo CA, et al. Effects of acitretin on the liver. J Am Acad Dermatol. 1999;41(4):584–588. 151. Kreiss C, Amin S, Nalesnik MA, Chopra K, Shakil AO. Severe cholestatic hepatitis in a patient taking acitretin. Am J Gastroenterol. 2002;97(3):775–777. 152. Roenigk HH. Liver toxicity of retinoid therapy. J Am Acad Dermatol. 1988;19(1 Pt 2):199–208. 153. Sherman SI, Gopal J, Haugen BR, et al. Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med. 1999;340(14):1075–1079. 154. Andersen WK, Feingold DS. Adverse drug interactions clinically important for the dermatologist. Arch Dermatol. 1995;131(4):468–473. 155. Baran R. [Therapeutic assessment and side-effects of the aromatic retinoid on the nail apparatus]. Ann Dermatol Venereol. 1982;109(4):367–371.

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PART V

Drugs Used in Conjunction with UV or Visible Light

23 Psoralen Plus Ultraviolet A Photochemotherapy and Other Phototherapy Modalities BHAVNIT K. BHATIA, HENRY W. LIM AND ILTEFAT H. HAMZAVI

QUESTIONS Q23.1 What is the pharmacologic importance of food intake and the hepatic ‘first-pass effect’ on methoxsalen bioavailability? (Pg. 264) Q23.2 In which part of the ultraviolet A (UVA) spectrum does methoxsalen have its maximum absorption? (Pg. 264) Q23.3 What is the risk of squamous cell carcinoma (SCC) from long-term psoralen plus UVA (PUVA) therapy and are these more biologically aggressive than actinically-induced SCC? (Pg. 266)

Q23.8 Does NB-UVB have a defined risk for nonmelanoma skin cancer? (Pg. 268) Q23.9 Does NB-UVB have a defined risk in pregnancy and nursing? (Pg. 268) Q23.10 What is the specific action spectrum of excimer laser? (Pg. 268) Q23.11 What is the maximum body surface area involvement optimal for treatment with excimer laser? (Pg. 268)

Q23.4 What is the true risk of melanoma from long-term PUVA photochemotherapy? (Pg. 266)

Q23.12 What are the three main indications for UVA-1 phototherapy? (Pgs. 269x2, 270)

Q23.5 What is the peak of the action spectrum for PUVA treatment of psoriasis? (Pg. 267)

Q23.13 Concerning UVA-1 potential adverse effects, (1) is photosensitive lupus erythematosus a contraindication to UVA1, and (2) what is the most common short-term adverse effect of UVA-1? (Pg. 270x2)

Q23.6 What is the optimal treatment frequency for narrow-band ultraviolet B (NB-UVB) phototherapy of psoriasis? (Pg. 267) Q23.7 What is the depth of skin penetration of UVA and UVB, and how does this relate to clinical decisions concerning the choice of PUVA versus NB-UVB? (Pg. 267)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R AE Adverse effects/events CYP Cytochrome P-450 MED Minimal erythema dose MOP Methoxypsoralen MPD Minimal phototoxic dose NB-UVB Narrow-band ultraviolet B NMSC Nonmelanoma skin cancer

PASI Psoriasis Area and Severity Index PUVA Psoralen plus ultraviolet A SCC Squamous cell carcinoma SPF Sun protection factor UV Ultraviolet UVA Ultraviolet A UVB Ultraviolet B

263

264

PA RT V

Drugs Used in Conjunction With UV or Visible Light

Introduction Psoralen plus ultraviolet A (PUVA) photochemotherapy is the photochemical interaction between a psoralen medication and ultraviolet A (UVA) (320–400 nm) radiation. This is most commonly known for its role in the treatment of psoriasis and has been used in over 30 other skin diseases. Psoralens, together with sunlight as a source of UVA radiation, have been used in the Middle East and Asia for treatment of vitiligo for at least 3000 years, and are still used in this original way in some countries today. The use of 8-methoxypsoralen (8-MOP) gained momentum after the seminal studies by Parrish and associates1 in the United States and Henseler and colleagues2 in Europe demonstrating that in combination with UVA radiation, it was efficacious in treating psoriasis, a treatment now commonly known as PUVA.

OCH3 O

O

O

Methoxsalen

• Fig. 23.1

Psoralen structure.

• BOX 23.1 Unique Features of Psoralen Pharmacology • • • • •

Insolubility in water Physical formulation influences absorption Food reduces absorption First-pass effect through liver Large interindividual variation in absorption

Psoralen Plus Ultraviolet A Photochemotherapy Pharmacology

Excretion

PUVA therapy requires UVA radiation in order for the psoralens to have a therapeutic effect. Therefore, the aim of treatment is to consistently produce a high level of drug in the target organ (skin) only at the time of exposure to UV radiation.

In humans, after oral administration of 40 mg of 8-MOP, 74% of the drug is excreted in urine, and 14% in feces.7 The excretion is rapid, being virtually complete within 12 hours. This is the reason that clinically, rigorous photoprotection must be practiced only on the day of administration of oral PUVA.

Structure The structure of 8-MOP is illustrated in Fig. 23.1.

Absorption Important features of psoralen absorption are listed in Box 23.1. Solubility in water varies, with 8-MOP being three times more water-soluble than 5-MOP (also known as bergapten).3 This is the reason that for a given dose, 8-MOP is two to three times more phototoxic than 5-MOP, reflected in the recommended 8-MOP dose of 0.4 to 0.6 mg/kg, and 5-MOP, 1.2 mg/kg. Because of a first-pass effect, 8-MOP doses below 20 mg in a 70-kg adult are not clinically effective. Q23.1 Intake of food before taking psoralens slows absorption and reduces the peak serum levels.4 Therefore, in clinical practice, patients are usually instructed to take a light meal before ingesting psoralens. There are significant intra- and interindividual variations in peak photosensitivity and in minimal phototoxic dose (MPD).5

Bioavailability With oral therapy, 75% to 80% of 8-MOP, and 98% to 99% of 5-MOP, respectively, is reversibly bound to serum albumin. Epidermal tissue binding is about 90% for 8-MOP and 99% for 5-MOP.6

Metabolism In terms of metabolism, 8-MOP is rapidly and almost completely metabolized in the liver; only small amounts of the parent compound can be detected in urine and bile.7

Photochemistry Q23.2 Ground state psoralen molecules are activated to the excited singlet state by absorption of photons in the UVA waveband, with peak absorption between 320 to 330 nm.8 The singlet state undergoes decay to the triplet state, and given that this is a relatively long-lived state, it is responsible for most photochemical effects. Two types of photochemical reaction occur. Type I (direct) photochemical reactions result in photoaddition of the compound to pyrimidines in deoxyribonucleic acid (DNA), forming monofunctional adducts and cross-linking of adjacent strands of DNA (bifunctional adducts) and conjugation of proteins. Type II (indirect) photochemical reactions result in the production of reactive oxygen species and free radicals that cause damage to cell membranes and cytoplasmic constituents.

Mechanism of Action PUVA therapy suppresses DNA synthesis through the formation of monoadducts and cross-links in DNA.9 It also causes selective immunosuppression.10 In addition, cells responsible for mediating a disease are selectively sensitive to be killed by exposure to PUVA therapy.11 Stimulation of melanocytes has been thought to be the explanation of the therapeutic effect seen in vitiligo.12

Clinical Use US Food and Drug Administration-Approved Indications. Box 23.21,2,13–76 lists indications and contraindications for PUVA. Psoriasis. PUVA therapy is successful in clearing about 70% to 100% of patients with plaque-type psoriasis in a course of up

CHAPTER 23

Psoralen Plus Ultraviolet A Photochemotherapy and Other Phototherapy Modalities

• BOX 23.2 Psoralen Plus Ultraviolet A Indications

and Contraindications US Food and Drug Administration-Approved Indications Psoriasisa 1–2,13–23 Mycosis fungoides/Sézary syndromea 24–28 Vitiligoa39–41

Other Dermatologic Uses Neoplastic

Other Pruritic Dermatoses

Histiocytosis X (Langerhans’ cell histiocytosis)29

Dermographism50 Aquagenic urticaria/pruritus51,52 Chronic urticaria53 Polycythemia vera54 Idiopathic pruritus Urticaria pigmentosa55,56 Prurigo nodularis

Papulosquamous/Dermatitis Atopic dermatitis30,31 Seborrheic dermatitis32 Chronic hand dermatitis20 Palmoplantar pustulosis20 Lichen planus33,34 Parapsoriasis27 Pityriasis lichenoides3–37 Lymphomatoid papulosis38

Photosensitivity Dermatoses Polymorphous light eruption42–46 Erythropoietic protoporphyria47 Solar urticaria48 Chronic actinic dermatitis49

Other Immunologic Dermatoses Alopecia areata57–61 Graft-versus-host disease62,63 Morphea64,65 Systemic sclerosis66,67

Miscellaneous Dermatoses Transient acantholytic dermatosis (Grover disease)68 Pigmented purpuric dermatoses69 Icthyosis linearis circumflexa70 Scleromyxedema71 Generalized granuloma annulare72–74

Contraindications Absolute

Relative

Pemphigus and pemphigoid75,76 Lupus erythematosus with photosensitivity Xeroderma pigmentosum Pregnancy Lactation History of idiosyncratic reaction to psoralen compound

Photosensitivity/photosensitizing medications Prior exposure to ionizing radiation or arsenic History or family history of melanoma History of skin cancer or chronic photodamage Severe cardiac, liver or renal disease Very young age

Pregnancy prescribing status—category C aMethoxsalen

capsules are approved for this indication.

to 30 treatments.1,2,13–17 Given that many PUVA clinical studies were done several decades ago, PASI scores, the current gold standard of clinical trials in psoriasis, were not used in these studies. However, extensive clinical experience would indicate that with the large majority of patients becoming clear or virtually clear, the vast majority of PUVA-treated patients would consistently exceed Psoriasis Area and Severity Index (PASI)-75 improvement. The therapy is also effective as a maintenance treatment, although the potential benefits of long-term use must be balanced against the potential toxicity of the therapy. Psoriasis of the palms and soles responds well to ‘hand-foot’ PUVA therapy.18–20 Broad-band (BB) UVB therapy is much less effective

265

than PUVA therapy in chronic psoriasis, whereas narrow-band (311 nm) UVB (NB-UVB) phototherapy is almost as effective as PUVA.21–23 Off-Label Dermatologic Uses Cutaneous T-cell Lymphoma. The patch and plaque stages

of mycosis fungoides respond to PUVA therapy in almost all cases after 20 to 30 treatments.24,25 Up to 50% of patients will remain in remission after a single course of treatment,26,27 but because of this high relapse rate a better approach is to use long-term maintenance treatment at a frequency of once or twice a month.27,28 Dermatitis and Papulosquamous Dermatoses. PUVA therapy has been commonly used for the treatment of atopic dermatitis.30,31 Lichen planus, both on the skin33 and in the mouth,34 responds to about 30 to 40 treatment sessions and maintenance treatment is usually not required. For oral lesions, a dental UVA light source is used. Vitiligo. Oral PUVA therapy has now been replaced by NBUVB phototherapy as the treatment of choice for vitiligo, as the latter is more effective than PUVA, is simpler to administer, and has a much lower risk of photocarcinogenesis.39–41 Other Immunologic Dermatoses. PUVA therapy has been used in alopecia areata with moderate success.57–61 Graft-versushost disease on the skin and in the mouth responds to PUVA therapy.62,63 Linear and generalized morphea respond reasonably well to PUVA therapy.64,65 Systemic sclerosis responds similarly.66,67 However, with the development of UVA-1 (340–400 nm) phototherapy, UVA-1 phototherapy has replaced PUVA as the UVbased treatment of choice for sclerodermoid skin conditions. Contraindications. There are only a few absolute contraindications and more relative contraindications to PUVA therapy (see Box 23.2). Lactation is listed because psoralens are secreted in breast milk. When a patient is taking a potentially photosensitizing medication, this fact should be noted; however, adjustment of the dose of UVA radiation is only required when potent phototoxic agents are involved, such as doxycycline and the fluoroquinolones. A 25% reduction in the UVA dose is usually adequate in these circumstances. If need be, PUVA can be administered to patients with aphakia, provided proper eye protection is in place.

Treatment Procedure Methoxsalen Administration. Patients take 8-MOP orally as capsules in a dose of 0.4 to 0.6 mg/kg body weight, 1 or 2 hours before exposure to UVA radiation. In general, 0.4 mg/kg is recommended for the Oxsoralen Ultra version of 8-MOP, because of its better and more predictable absorption. The lower dose reduces the problem of nausea and the 1-hour interval is more convenient for patients. The medication should be taken 30 minutes after a light meal, which would reduce nausea associated with 8-MOP. The pre-8-MOP meal should be kept consistent to minimize the fluctuation in serum levels. Ultraviolet A Radiation. The doses of UVA radiation are usually determined by skin phototype. If disease is present only on the hands and feet, a hand and foot PUVA unit can be employed. Clearance Schedule. Treatments are usually given two or three times weekly at least 48 hours apart to permit evaluation of any erythema resulting from the preceding treatment. If severe

266

PA RT V

Drugs Used in Conjunction With UV or Visible Light

erythema is present and widespread, treatment should be held until it subsides. Maintenance Schedule. The final clearance dose of radiation is held constant and the frequency of treatment is gradually reduced. If a significant (>5%) amount of psoriasis begins to return, the frequency of treatment can be increased or a clearance schedule can be restarted. Combination Treatments. Although data are contradictory, it is common practice to use combination treatments with PUVA therapy, which could potentially reduce overall exposure to UVA radiation. Protection. Eye protection with UVA-blocking glasses is required when the patient is exposed to sunlight on the day of treatment, from time of psoralen ingestion until sunset that day. Regular use of these glasses should be done even when patients are exposed to window-glass filtered sunlight, such as when driving. On the day of treatment, after ingestion of psoralens, photoprotection should be practiced, including application of broad-spectrum sunscreen with sun protection factor (SPF) of ≥30 on exposed areas, taking care that sunscreen is not on the skin when UVA exposure is administered. The amount of UVA emitted by fluorescent lights or a computer screen is not adequate to induce phototoxic reaction, therefore photoprotection, including the use of UV-blocking glasses, is not necessary in these settings. Men should wear a jockstrap or another means of genital protection. Short-Term Adverse Effects. Short-term AE are listed in Box 23.3.77 Nausea is a common AE and clearly correlates with the serum level of the drug. As a first step, nausea can usually be relieved by having the patient eat a light meal before ingestion of 8-MOP, given that food reduces and slows absorption. Dosage can also be divided over 15 minutes. The next step is to reduce the dose by one capsule (10 mg). Lastly, an antiemetic is sometimes (uncommonly) required. Long-Term Adverse Effects. Long-term AE are listed in Box 23.4.78–97 Photoaging is the most consistent AE; this manifests as freckling, dyspigmentation, wrinkling, and the formation of actinic keratoses. The so-called PUVA lentigines, which are usually large, dark, and irregularly shaped,79 form part of this chronic photoaging spectrum. Nonmelanoma Skin Cancer Risk. Q23.3 Nonmelanoma skin cancer (NMSC) is markedly increased in patients who receive high cumulative UVA exposure. This risk is mainly confined to Caucasians. In a prospective US multicenter study that followed nearly 1400 patients treated with PUVA therapy for 30 years, about one-fourth developed squamous cell carcinoma (SCC) of the skin, with smaller increases in basal cell carcinomas.80 This increased risk of NMSC is dependent on number of treatments, and the risk is particularly evident in patients receiving more than 150 treatments, with a higher risk of multiple SCC in patients receiving over 350 treatments. An increased risk of SCC on male genitalia was also found in the US multicenter study,90 prompting the recommendation to cover this region during treatment. This has not been reported in studies from Europe. Melanoma Risk. Q23.4 In the US cohort, an increased incidence of melanoma was reported, which was detected in patients who had been followed for over 15 years. This was primarily found in patients who had received more than 250 treatments.91 In contrast, this risk of melanoma has not been

• BOX 23.3 Short-Term Adverse Effects of Psoralen

Plus Ultraviolet A Therapy77 Phototoxic Reactions • Symptomatic erythema • Pruritus • Subacute phototoxicity • Photoonycholysis • Koebner phenomenon • Friction blisters on hands and feet • Ankle edema

Attributed to Methoxsalen Alone • Gastrointestinal disturbance • Central nervous system disturbance • Bronchoconstriction • Hepatic toxicity • Drug fever • Exanthems Other Adverse Effects • Cardiovascular stress • Herpes simplex recurrences • Photosensitive eruptions

Data from Morison WL, Marwaha S, Beck L. PUVA-induced phototoxicity: Incidence and causes. J Am Acad Dermatol. 1997;36:183–185.

• BOX 23.4 Long-Term Adverse Effects of Psoralen

Plus Ultraviolet A Therapy Photoaging78,79 Nonmelanoma skin cancer80–89 Melanoma • ‘Negative’ studies81–88 • ‘Positive’ study91 • Single case reports92–97

confirmed in numerous other studies.81-88,98 Continued observation of patients and careful cohort studies are required to confirm this finding. Drug Interactions. Phototoxic agents such as doxycycline and the fluoroquinolones may augment the phototoxicity of psoralens.99 Drugs that activate cytochrome P-450 (CYP) enzymes in the liver may reduce the effectiveness of the treatment through enhanced metabolism of 8-MOP; this is often seen with the CYP enzyme inducers carbamazepine and phenytoin.100 Monitoring Guidelines. A complete skin examination is essential before commencing treatment. An ophthalmologic examination should be obtained close to baseline. Routine laboratory tests are not required. Complete skin examinations should be performed at least every 6 months while on PUVA therapy. Given the persistent risk of skin cancer after cessation of phototherapy, complete skin examinations should be performed at least yearly on a long-term basis. Other Forms of Psoralen Plus Ultraviolet A Therapy. Topical PUVA therapy has also been used for various skin conditions. 8-MOP solution, usually diluted 1 in 10 parts with aquaphor to give a 0.1% preparation, is applied 20 to 30 minutes before exposure to UVA radiation. Because of the narrow therapeutic window, to minimize unwanted phototoxicity, the initial exposure dose is 0.5 J/cm2 with increments of 0.25 J/ cm2. Dosing is often capped at 4 J/cm2 to minimize severe phototoxicity.

CHAPTER 23

Psoralen Plus Ultraviolet A Photochemotherapy and Other Phototherapy Modalities

A very dilute solution (generally 0.33–0.5 mg/L) of psoralen in bath water (for whole-body exposure) or a basin (for treatment of the hands and feet) is used as an alternative to oral administration of the 8-MOP in some centers around the world, although this is rarely used in the United States. The main limitation of bath PUVA is the resources needed: a bathtub, the treatment of patients with UVA within minutes of bathing, and housekeeping staff to clean the bathtub after each patient.

Narrow-Band Ultraviolet B Phototherapy Introduction NB-UVB phototherapy has largely replaced the older BB-UVB phototherapy in the treatment of psoriasis and other diseases because of its greater effectiveness and safety.101 The fluorescent lamp used for this treatment (TL01, Philips Lighting Company) has a narrow emission spectrum centered around 311 nm. Q23.5 The scientific basis for using this lamp was the demonstration that the peak of the action spectrum for phototherapy of psoriasis was in the 300 to 320 nm waveband.102,103 It is possible that this is the peak of the action spectrum for phototherapy of other NB-UVB responsive skin diseases, but this has not been established.

Clinical Use Psoriasis. Q23.6 Most studies report NB-UVB clearance rates (> fluconazole (only doses >200 mg)

Same

Calcium channel blockers

Diltiazem, verapamil

Same

Calcineurin inhibitors

Cyclosporine, tacrolimus (oral)

Same

HIV-1 protease inhibitors

Ritonavir, indinavir > nelfinavir, saquinavir

Same

Foods

Grapefruit juice, grapefruit

Same

P-glycoprotein inhibitors

Clarithromycin, azithromycin, erythromycin, many others

May ↑ serum levels vismodegib, various toxicities

Triazoles

Fluconazole

Modest ↑ serum levels vismodegib

Antibiotics

Trimethoprim/sulfamethoxazole

Same

Antacids

H2 antihistamines, proton pump inhibitors, calcium/magnesium containing

May ↓ absorption of vismodegib conceptually (no formal studies)

Anticonvulsants

Phenytoin, carbamazepine, phenobarbital

CYP3A4 inducers may ↓ serum levels of sonidegib, possible loss efficacy

Rifamycins

Rifampin, rifabutin

Same

Relatively High-Risk Drug Interactionsb

Lower-Risk Drug Interactions

aThe

dramatic increase in number of drug interactions in medicine requires some degree of selectivity in these tables (common usage, relative risk, focus on outpatient treatment) highest-risk drug interactions indicated in bold italics. CYP, Cytochrome P-450; HIV, human immunodeficiency virus. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications; 2019. (http://www.hanstenandhorn.com/). bOverall

TABLE Key Laboratory Abnormalities in Patients 38.5 Taking Sonidegiba SONIDEGIB 200 mg (N = 79)

All Grades (%)

Grade 3 (%)

92b 61

0 8

51 43 19

4 13 4

19

4

16

1

32 28

0 3

Chemistry Increased serum creatinine Increased serum creatine kinase (CK) Hyperglycemia Increased lipase Increased alanine aminotransferase Increased aspartate aminotransferase Increased amylase

Hematology Anemia Lymphopenia

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aKey

laboratory abnormalities in patients taking sonidegib 200 mg dosing in a randomized double-blind, multiple cohort trial in which 229 patients received sonidegib at either 200 mg (n = 79) or 800 mg (n = 150) daily. Laboratory abnormalities are based on worse posttreatment laboratory value regardless of baseline.18 bThe serum creatinine level remained within normal range in 76% (60/79) of patients.

5. Danhof R, Lewis K, Brown M. Small molecule inhibitors of the hedgehog pathway in the treatment of basal cell carcinoma of the skin. Am J Clin Dermatol. 2018;19(2):195–207. 9. Hedgehog inhibitor approved for BCC. Cancer Disc. 2015;5(10):1011.

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13. Bhutani T, Abrouk M, Sima CS, et al. Risk of cutaneous squamous cell carcinoma after treatment of basal cell carcinoma with vismodegib. J Am Acad Dermatol. 2017;77(4):713–718. 14. Sekulic A, Migden MR, Basset-Seguin N, et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer. 2017;17(1):332. 16. Genetech USA. ERIVEDGE (vismodegib) capsules, for oral use [prescribing information]. Revised January 2019. Available at: https://www.accessdata.fda. gov/drugsatfda_docs/label/2012/203388lbl.pdf. Accessed February 21, 2019.

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42. Luo JD, Hu TP, Wang L, Chen MS, Liu SM, Chen AF. Sonic hedgehog improves delayed wound healing via enhancing cutaneous nitric oxide function in diabetes. Am J Physiol Endocrinol Metab. 2009;297(2):E525–E531. 43. Lucero OM, Fitzmaurice S, Thompson C, Leitenberge J. A case illustrating successful eradication of recurrent, aggressive basal cell carcinoma located in a scar with vismodegib. Dermatol Online J. 2018;24(2). 44. Chang AL, Lewis KD, Arron ST, et  al. Safety and efficacy of vismodegib in patients aged ≥65 years with advanced basal cell carcinoma. Oncotarget. 2016;7(46):76118–76124. 45. Paladini RD, Saleh J, Qian C, Xu GX, Rubin LL. Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway. J Invest Dermatol. 2005;125(4):638–646. 46. Kumari A, Ermilov AN, Grachtchouk M, et al. Recovery of taste organs and sensory function after severe loss from Hedgehog/ Smoothened inhibition with cancer drug sonidegib. Proc Natl Acad Sci U S A. 2017;114(48):E10369–E10378. 47. Kumari A, Ermilov AN, Allen BL, Bradley RM, Dlugosz AA, Mistretta CM. Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation. J Neurophysiol. 2015;113(3):1034–1040. 48. Mohan S, Chang J, Li S, Henry AS, Wood DJ, Chang AL. Increased risk of cutaneous squamous cell carcinoma after vismodegib therapy for basal cell carcinoma. JAMA Dermatol. 2016;152(5):527–532. 49. Basset-Seguin N, Sharpe HJ, de Sauvage FJ. Efficacy of Hedgehog pathway inhibitors in basal cell carcinoma. Mol Cancer Ther. 2015;14(3):633–641.

50. Atwood SX, Sarin KY, Whitson RJ, et al. Smoothened variants explain the majority of drug resistance in basal cell carcinoma. Cancer Cell. 2015;27(3):342–353. 51. Chen B, Trang V, Lee A, et al. Posaconazole, a second-generation triazole antifungal drug, inhibits the hedgehog signaling pathway and progression of basal cell carcinoma. Mol Cancer Ther. 2016;15(5):866–876. 52. Fife D, Laitinen MA, Myers DJ, Landsteiner PB. Vismodegib therapy for basal cell carcinoma in an 8-year-old Chinese boy with xeroderma pigmentosum. Pediatr Dermatol. 2017;34(2): 163–165. 53. National Library of Medicine; National Center for Biotechnology Information. Compound summary for CID 55283 Sporanox (itraconazole). PubChem (open chemistry database). Modified February 16, 2019. Available at: https://pubchem. ncbi.nlm.nih.gov/compound/55283. Accessed February 21, 2019. 54. National Library of Medicine; National Center for Biotechnology Information. Compound summary for CID 468595 Noxafil (posaconazole). PubChem (open chemistry database). Modified February 16, 2019. Available at: https://pubchem. ncbi.nlm.nih.gov/compound/468595. Accessed February 21, 2019. 55. National Library of Medicine; National Center for Biotechnology Information. Compound summary for CID 14888 arsenic(III) trioxide. PubChem (open chemistry database). Modified February 16, 2019. Available at: https://pubchem.ncbi.nlm.nih.gov/ compound/14888. Accessed February 21, 2019.

39 Drugs for the Skinternist MEGAN N. LANDIS AND DAVID R. ADAMS

QUESTIONS Q39.1 What is the most important adverse effect from the most potent bisphosphonates (such as etidronate)? (Pg. 431) Q39.2 What are the mechanisms of action by which bisphosphonates prevent and treat osteoporosis? (Pg. 431)

Q39.6 What serum test should be monitored periodically to determine the adequacy of levothyroxine replacement in bexarotene-induced hypothyroidism? (Pg. 437)

Q39.3 What are the reasons that oral bisphosphonates must be taken in a fasting state and in an upright position? (Pg. 435)

Q39.7 Why was cerivastatin taken off the market by the US Food and Drug Administration (FDA); what is the risk of this same complication in the remaining ‘statins’? (Pgs. 438, 440)

Q39.4 What are typical doses for (1) calcium, (2) vitamin D, and (3) various bisphosphonates in the prevention and management of corticosteroid-induced osteoporosis? (Pg. 436)

Q39.8 Concerning drug interactions with the statins, which drugs in this class do not interact with drugs (such as cyclosporine) metabolized by the CYP3A4 pathway? (Pg. 438)

Q39.5 What is the unique subtype of hypothyroidism from bexarotene, and what is the mechanism of action regarding this complication? (Pg. 437)

Q39.9 In which clinical settings has fenofibrate occasionally been associated with myopathy and rhabdomyolysis? (Pg. 442) Q39.10 Concerning vitamin D therapy (1) what is the mechanistic role of vitamin D in corticosteroid osteoporosis prevention, and (2) what malignancies are possibly reduced by significant vitamin D intake? (Pg. 444)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R AE Adverse effect(s) BMD Bone mineral density BPP Bisphosphonates CK Creatine kinase (= creatine phosphokinase) CS Corticosteroids CsA Cyclosporine (A) CTCL Cutaneous T-cell lymphoma CYP Cytochrome P-450 DEXA Dual-energy x-ray absorptiometry (scan) GC Glucocorticoid GI Gastrointestinal GCIO Glucocorticoid-induced osteoporosis HDL High-density lipoprotein HMGCoA 3-hydroxy-3-methylglutaryl-coenzyme A (reductase) IDL Intermediate density lipoprotein IFN Interferon IV Intravenous

Introduction Three of the most commonly used systemic drugs or drug classes in dermatology, corticosteroids (CS), retinoids, and cyclosporine (CsA), present the challenge of managing their adverse effects (AE). The prevention and therapy of CS-induced osteoporosis 430

LDL Low-density lipoprotein NSAID Nonsteroidal anti-inflammatory drug(s) OCIF Osteoclastogenesis inhibitory factor PPAR Peroxisome proliferator activator receptors PTH Parathyroid hormone PUD Peptic ulcer disease RAR Retinoic acid receptor RXR Retinoid X receptor SLE Systemic lupus erythematosus T3 Triiodothyronine T4 Tetraiodothyronine (= thyroxine) TG Triglycerides TNF Tumor necrosis factor TRH Thyrotropin-releasing hormone TSH Thyroid-stimulating hormone (= thyrotropin) VLDL Very low-density lipoprotein

(CSIO), hypothyroidism associated with bexarotene, and retinoidor CsA-induced hyperlipidemia are herein discussed. Featured in this chapter are the bisphosphonates (BPP), levothyroxine, the ‘statins,’ fenofibrate, and ezetimibe. A brief section on vitamin D controversies concludes the chapter.

CHAPTER 39

Therapy for Corticosteroid-Induced Osteoporosis

Pharmacology Structure. Three generations of BPP are commercially available

and variably indicated for the treatment of osteoporosis (including CSIO), hypercalcemia of malignancy, bone metastases, heterotopic ossification, and Paget disease.5 Members of this class include etidronate (Didronel), clodronate (not available in the United States), pamidronate (Aredia), alendronate (Fosamax), ibandronate (Boniva), risedronate (Actonel), zoledronate (Zometa), and zoledronic acid (Aclasta, Reclast). The BPP differ by their route and frequency of administration, as shown in Table 39.1. Zoledronic acid is the newest oral BPP approved in the United States for the treatment of postmenopausal osteoporosis. Absorption and Bioavailability. Absorption of oral BPP through the upper gastrointestinal (GI) tract occurs rapidly, over approximately 1 hour. Their absorption through the intestines is poor. BPP must be administered following an overnight fast and taken 30 to 60 minutes before breakfast.5 Coadministration

431

NH2 CH2

Bisphosphonates Chronic use of systemic CS is associated with the development of osteoporosis and an increased fracture risk. Osteoporosis may be diagnosed by finding evidence of diminished bone mineral density (BMD) as measured by dual energy x-ray absorptiometry (DEXA). Much later signs of osteoporosis include the development of an osteoporotic fracture, loss of height, or kyphosis indicative of vertebral fractures.1 The estimated prevalence of CSIO is 50% among treated individuals.2 The relative risk of a hip fracture in patients on long-term prednisone 7.5 mg daily is 2.27 (confidence interval [CI], 1.94– 2.66), and the vertebral fracture risk is 5.18 (CI, 4.25–6.31).3 Bone loss, which occurs most rapidly during the first 6 months of prednisone therapy, results from inhibited bone formation and enhanced osteoclast-mediated bone resorption.1 Systemic CS promoted bone loss is caused by: 1. Reducing calcium absorption; 2. Increasing renal calcium excretion; 3. Reducing levels of testosterone in men and estrogen in women, by reducing pituitary secretion of gonadotropins; 4. Inhibiting osteoprotegerin, also known as osteoclastogenesis inhibitory factor (OCIF).4 OCIF, a member of the tumor necrosis factor (TNF) receptor superfamily, is a cytokine that inhibits the differentiation of and resorption by osteoclasts, and thus increases BMD and bone volume. BPP are antiresorptive agents with an affinity for hydroxyapatite crystals in bone. At the cellular level, they inhibit osteoclast activity. The rate of bone turnover is decreased as early as 14 days, and maximally within 6 months of treatment with BPP.5 Q39.1 Etidronate, the first BPP developed for clinical use, is the most potent inhibitor of mineralization, which has equal inhibition of bone resorption. All other BPP have bone resorption greater than inhibition of mineralization; drug dose is a key factor as well. This quality is now viewed as a disadvantage, because clinical experience has revealed that such sustained inhibition leads to osteomalacia. The second- and third-generation BPP have been developed to minimize inhibition of mineralization, while maintaining the ability to prevent bone resorption.6 Fig. 39.1 shows the drug structure for several BPP.

Drugs for the Skinternist

CH2

HO

O

CH2 O

P

C

P

OH

OH

OH

ONa • 3H2O

Alendronate

HO

O

OH

O

P

C

P

OH

CH2

OH

ONa

• 2.5 H2O N Risedronate

• Fig. 39.1

Chemical structures of alendronate, risedronate.

with calcium, antacids, or medications containing divalent cations, interferes with their absorption. Mean bioavailabilities of standard oral doses of alendronate, risedronate, and ibandronate were 0.6% compared with intravenous (IV) dosing. Approximate plasma protein binding of BPP includes: (1) risedronate 24%, (2) alendronate 78%, (3) ibandronate 85% to 90%,5 and, (4) zoledronic acid 22%.6 Metabolism and Excretion. Alendronate, risedronate, ibandronate, and zoledronic acid are not systemically metabolized. Approximately half of the absorbed dose of either risedronate or alendronate is excreted unchanged in the urine within 24 and 72 hours, respectively. Steady-state conditions in the serum are observed within 57 days of daily dosing of risedronate. Plasma concentrations of alendronate, following therapeutic oral doses, are too low for analytical detection. Once absorbed, the serum concentration-time profile for risedronate is multiphasic; its initial half-life is 1.5 hours and its terminal exponential half-life, thought to represent dissociation of risedronate from bone, is 480 hours (20 days). For alendronate, the terminal half-life in humans is estimated to exceed 10 years, also reflecting its slow release from bone. Unabsorbed drug is eliminated unchanged in the feces.5,7 For ibandronate, the terminal half-life of the 150-mg tablet ranges from 37 to 157 hours. Renal excretion accounts for 50% to 60% of the total clearance of ibandronate.5 Zoledronic acid concentration in the plasma decreases rapidly after infusion, owing to increased absorption of the drug by the bone. Small amounts can be detected in the plasma several days after the infusion, as the drug is gradually released during bone turnover. It is excreted intact into the urine and can be detected beginning 24 hours after the infusion until 28 days postinfusion.8 Mechanism of Action. Q39.2 BPP are incorporated into bone matrix. Aminobisphosphonates, such as alendronate, directly inhibit multiple steps in cholesterol synthesis, which are required for prenylation (the addition of hydrophobic molecules to a

432

PA RT V I I

Miscellaneous Systemic Drugs

TABLE The Bisphosphonates 39.1

Generic Name

Trade Name

Generation

Route of Administration

Etidronate

Didronel

First

Oral

400 mg/day for 14 days, repeated every 15 weeks (offlabel use in the US)

Pamidronate

Aredia

Second

IV

90 mg initial IV dose, followed by 30 mg IV every 3 months (off-label use in the US)

Alendronate

Foxamax

Third

Oral

Prevention: 5 mg once daily or 35 mg once weekly (10 mg once daily if postmenopausal and off estrogen) Treatment: 10 mg once daily or 70 mg once weekly.

Ibandronate

Boniva

Third

Oral, IV

2.5 mg once daily or 150 mg once monthly or 3 mg IV every 3 months

Risedronate

Actonel

Third

Oral

5 mg once daily or 35 mg once weekly or 150 mg once monthly

Tiludronate

Skelild

Third

Oral

Not applicable.

Zoledronate

Zometa

Third

IV

Not applicable.

Zoledronic acid

Reclast, Aclasta

Third

IV

Prevention: 5 mg IV once every 2 years Treatment: 5 mg IV once yearly

Dosing for Corticosteroid-Induced Osteoporosis

IV, Intravenous. Data from Physician’s Desk Reference Online 2004-2005. (Online). Available at: http://www.PDR.net.

protein to facilitate protein attachment to the cell membrane) of osteoclast-associated proteins. Ultimately, BPP inhibit bone resorption and increase bone volume and strength by slowing the formation and dissolution of hydroxyapatite crystals.7,9 The mechanism by which nitrogen-containing BPP promote osteoclast apoptosis is distinct from that of the nonnitrogen-containing BPP. As elegantly illustrated in recent studies, nitrogen-containing BPP bind to and inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway, critical to the production of cholesterol, other sterols, and isoprenoid lipids6,7 (Fig. 39.2). As such, the posttranslational modification (isoprenylation) of proteins (including the small guanosine triphosphate–binding proteins Rab, Rac, and Rho, which play central roles in the regulation of core osteoclast cellular activities including stress fiber assembly, membrane ruffling, and survival) is inhibited,8 ultimately leading to osteoclast apoptosis.9 Interestingly, whereas farnesyl pyrophosphate synthase is ubiquitously expressed in mammalian cells and has a critical role in lipid production, cellular apoptosis induced by nitrogencontaining BPP appears to occur only in osteoclasts. This is likely a direct function of the ability of BPP to selectively adhere to and be retained within bone before endocytosis within osteoclasts during osteoclast-mediated bone mineral dissolution and matrix digestion.10 Clinical Use Indications. It is important to know when BPP is indicated,

whether prescribing or collaborating with other providers. For patients with an anticipated 3 months or longer course of CS, screening should take place at baseline for osteopenia (T-score between –1 and -2.5) and osteoporosis (T-score < –2.5) with a DEXA scan to estimate BMD. Oftentimes, clinical findings and DEXA scan results can guide management. Additional tools are

available, such as the World Health Organization fracture prevention algorithm (FRAX) to prevent 10-year fracture risk, but this tool does underestimate CS-induced fracture risk.11 (FRAX is available at http://www.shef.ac.uk/FRAX/). There is no current model to accurately predict fracture risk in premenopausal women and men under age 50 years. Fig. 39.3 shows how to approach treating CSIO using BPP. Method of Administration Osteoporosis Prevention. Alendronate has been shown to

increase BMD in patients receiving CS therapy in two 48-week randomized, controlled trials of 477 women aged 17 to 83 years, receiving CS therapy.12 Subjects were randomized to placebo, 5 mg daily alendronate, or 10 mg daily alendronate. All patients received 800 to 1000 mg elemental calcium and 250 to 500 IU vitamin D daily. There were fewer new vertebral fractures in the alendronate groups (overall incidence 2.3%) than in the placebo group (3.7%), but this number did not reach statistical significance (relative risk 0.6; 95% CI, 0.1–4.4). There were no differences in serious AE, although a small increase in mild upper GI effects was noted in the 10-mg alendronate group.8 BPP have been shown by meta-analysis to be the most effective therapy to increase BMD in patients receiving CS therapy, with a 4.6% difference in percent change in the lumbar spine relative to no treatment or treatment with calcium. The efficacy of BPP was further enhanced when used in combination with vitamin D (6% difference in BMD). BPP, including alendronate, risedronate, and ibandronate, have also been shown to reduce fracture risk in patients receiving CS treatment. A meta-analysis of nine randomized clinical trials that each included more than 50 patients in each treatment arm found that the overall reduction in risk or vertebral fractures was 37% (CI, 0.49–0.80) (Box 39.1).13 Osteoporosis Treatment. BPP are first-line for treatment of CIOP and evidence supports their efficacy in preventing

Drugs for the Skinternist

CHAPTER 39

CH3 O

CH3

OH

CH

CH2

N

O

CH

CH

CH2

NHC

OH

N CH2

CH2

433

N

– • Ca2+ • 3H2O

F

2

Atorvastatin F

O N OH H3C

O–

OH

Na+

CH3

Fluvastatin O

HO

O O H O

H3C

H

H CH3

CH3

H3C Lovastatin

• Fig. 39.2

Chemical structures of atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin.

and treating bone loss in these patients.14 They should be considered in all patients taking CS chronically who have accelerated bone loss or a history of fragility fractures. Those most likely to benefit include those at highest fracture risk, including patients over age 50 years with known osteoporosis, osteopenia taking 7.5 mg or more of prednisone for 3 months or longer, and osteopenia taking any dose of prednisone considered high risk. Evidence is less well defined in premenopausal women and younger men. One must consider potential long-term risks and teratogenicity when considering therapy in these patients. Alendronate or risedronate are typically first-line agents, and IV zoledronic acid is an option for patients who cannot tolerate oral BPP. BPP should be avoided in patients with

creatinine clearance less than 30 mL/min, and such patients should be referred to a specialist for comanagement. Dosing and counseling details can be found in Box 39.1. Several studies provide evidence of the efficacy of these medications and their benefits.15–18 Monthly Ibandronate. Monthly ibandronate is considered and alternative therapy but is not first line. It has been shown to decreased vertebral fracture risk and to increase BMD in women with postmenopausal osteoporosis.5 However, there is not currently specific data to support its use first-line for treatment of CSIO. A study in rabbits demonstrated potential to prevent and treat CSIO in animals,19 but human studies are lacking. Contraindications and Use in Pregnancy. BPP may cause upper GI disorders, such as dysphagia, esophagitis, and esophageal

434

PA RT V I I

Miscellaneous Systemic Drugs

OH NaOOC HO

O

O

O

H CH3

CH3

HO

Pravastatin F

OH

OH

O

Ca2+ O–

N

N

N SO2Me

2

Rosuvastatin O

HO

O O

O

H3C

CH3

H3C

H

H

H CH3

H3C Simvastatin

• Fig. 39.2, cont’d or gastric ulcer. Oral BPP should not be used in patients with serious esophageal disease. Other contraindications include hypocalcemia, renal insufficiency, osteomalacia, and hypersensitivity to any component of the product.5,9,12,13,15 Risedronate and alendronate are classified as pregnancy category C. At least two of the parenteral BPP, pamidronate and zolendronic acid, are rated pregnancy category D.5 Regarding the oral formulations, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant during or relatively soon after completing a course of a BPP.9 BPP should be avoided during pregnancy and lactation, and used only when

the potential benefit justifies the potential risk to both mother and fetus.20 Of note, BPP are lipid soluble and may be stored in body fat for months to years. With the potential for fetal harm with abnormal bone development, as seen in animal studies, caution should be used when considering treatment of premenopausal women who may still become pregnant.21 Adverse Effects Overall Adverse Effects. The AE profile of the BPP class is

described in Table 39.2. Abdominal pain is the most common AE, followed less commonly by nausea, heartburn, irritation or

CHAPTER 39

Drugs for the Skinternist

435

Initiation of Glucocorticoids

Counsel the patient regarding fracture risk Assess and address modifiable risk factors Evaluate baseline bone density (DEXA scan) Begin supplemental calcium and vitamin D

Low or Intermediate Risk T-score -1 to -2.5 and 10-year fracture risk 40

>40

40

>40

>40

Dosage associated with >40% LDL reduction (mg/day)

n/a

n/a

>40

>20

n/a

>5

4

Serum LDL reduction produced by 40 mg daily (%)

34

34

41

50

24

63

n/a

Serum triglyceride reduction (%)

5–22

7–10

10–20

16–26

8–12

16–28

14–22

Serum HDL increase (%)

6–18

6–8

6–8

4–6

6–10

8–10

4–8

Plasma half-life (h)

2

1–2

1–2

14

1.2

20

11

Effect of food on absorption of drug

Increased absorption

Decreased absorption

None

None

Negligible

Decreased rate, but fully absorbed

Decreased rate, but fully absorbed

Penetration of central nervous system

Yes

No

Yes

No

No

Yes

Yes

Systemic bioavailability

> clarithromycin > azithromycin

CYP3A4 inhibitors which ↑ statin drug levels and resultant toxicity—myopathy, rhabdomyolysisa

Imidazole, triazole antifungals

Ketoconazole >> itraconazole > fluconazole (only >200 mg daily)

same

Calcium channel blockers (CCB)

Diltiazem, verapamil

same (all CCB are CYP3A4 substrates; these two drugs are also inhibitors)

HIV-1 protease inhibitors

Ritonavir, indinavir >> saquinavir, nelfinavir

same

Nutritional products

Grapefruit, grapefruit juice

same

Fluoroquinolones

Ciprofloxacin

Weak CYP3A4 inhibitor

Antidysrhythmics

Amiodarone

same

H2 antihistamines

Cimetidine

same

Relatively High-Risk Drug Interactionsa (CYP2C9 substrates—fluvastatin, rosuvastatin, pitavastatin) Triazoles

Fluconazole

Of the azoles, fluconazole is primary CYP2C9 inhibitor even at low doses; risk myopathy

Antidysrhythmics

Amiodarone

Weak CYP2C9 inhibitor

Antiparasitic

Metronidazole

same

SSRI antidepressants

Fluoxetine, fluvoxamine

same

Lower-Risk Drug Interactions—CYP3A4 Aforementioned Substrates Rifamycin antibacterials

Rifampin, rifabutin, rifapentine

CYP3A4 induction with resultant ↓ statin drug levels and loss efficacy; this effect begins in 1–2 weeks

Aromatic anticonvulsants

Phenytoin, carbamazepine, phenobarbital

same (also primidone, ethosuximide)

Antifungals

Griseofulvin

Weak CYP3A4 inducer

Lower-Risk Drug Interactions—CYP2C9 Aforementioned Substrates Rifamycin antibacterials

Rifampin (mod.), rifabutin (weak)

CYP2C9 induction with resultant ↓ statin drug levels and loss efficacy; this effect begins in 1–2 weeks

Aromatic anticonvulsants

Phenytoin, carbamazepine, primidone (all 3 weak)

same

Antifungals

Griseofulvin (weak)

same

Habits

Alcohol

CYP2C9 inducer—dose, chronicity dependent

The dramatic increase in number of drug interactions in medicine requires some degree of selectivity in these tables (common usage, relative risk, focus on outpatient rx). CYP, Cytochrome P-450; HIV, human immunodeficiency virus; SSRI, selective serotonin reuptake inhibitor. aOverall highest-risk drug interactions indicated in bold italics. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. (http://www.hanstenandhorn.com/).

Clinical Use Indications Method of Administration. Fenofibrate is available as Tricor in

a 48- and 145-mg tablet, taken once daily with or without food. It is also available as Lofibra in 67-, 134-, and 200-mg micronized capsules, which are taken once daily with food. The initial dose of Lofibra for the treatment of primary hypercholesterolemia or mixed hyperlipidemia in adult patients is 200 mg daily. The initial dose for hypertriglyceridemia in adult patients is 67 to 200 mg daily. When using Tricor for adults with primary hypercholesterolemia or mixed dyslipidemia, the initial dose is 145 mg daily. The initial dose of Tricor for hypertriglyceridemia is 48 to 145 mg daily.

Hypertriglyceridemia. The effects of fenofibrate therapy in patients with hypertriglyceridemia and normal cholesterol levels, at dosages equivalent to 160 mg daily, include decreased VLDL TG and VLDL cholesterol. However, patients with elevations in both cholesterol and TG have developed increasing LDL fractions during fenofibrate therapy. For this reason, patients must be placed on an appropriate lipid-lowering diet before receiving fenofibrate, and should continue this diet during treatment.5 Clinical trials have evaluated fenofibrate as a monotherapy, but also as part of a combination therapy for combined hyperlipidemia. Fenofibrate has been combined safely and successfully both with ezetimibe,80 a cholesterol absorption inhibitor, and with

442

Miscellaneous Systemic Drugs

PA RT V I I

Baseline labs: Complete blood count, liver function tests, CK, lipid panel, pregnancy test. Commence diet therapy

TG > 250 mg/dL Normalize lipids with LLA before initiating bexarotene

TG < 250 mg/dL Start low dose LLA

Start bexarotene in 1 week 300 mg/m2/day Monitor labs weekly

Start bexarotene in 1 week 300 mg/m2/day Monitor all labs weekly TG > 400–800 mg/dL Increase LLA dose or TG > 800 mg/dL Hold bexarotene, increase LLA dose, resume bexarotene at same or lower dose when TG < 400 mg/dL

Labs stable Monitor labs monthly

• Fig. 39.4

Therapeutic guidelines for the treatment of hypertriglyceridemia during therapy with bexarotene (CK, Creatine phosphokinase; TG, triglycerides; LLA, lipid lowering agent).

CH3

CH3

• BOX 39.4 Drug Risks Profile—Fibric Acid

Derivatives—Fenofibrate & Gemfibrozil CI

C

O

C

C

O

C

H

Contraindications O

CH3

O

CH3

Fenofibrate

• Fig. 39.5

Chemical structure of fenofibrate.

Hypersensitivity to fibrates or components of formulation Severe renal impairment, endstage renal disease Breast feeding (fenofibrate only)

Active liver disease, persistently abnormal liver function Pre-existing gall bladder disease

Boxed Warnings

simvastatin.81 Table 39.6 reviews the selection of lipid-lowering agents according to the predominant lipid abnormality. Contraindications and Use in Pregnancy. Fenofibrate is contraindicated in patients who exhibit hypersensitivity to the drug or its inactive ingredients. It is contraindicated in patients with hepatic dysfunction, including primary biliary cirrhosis and pre-existing gallbladder disease, and in severe renal dysfunction. Fenofibrate is pregnancy category C; there are no well-controlled studies in pregnant women. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus5,7 (see Box 39.4). Adverse Effects Overall Adverse Effects. Fibric acid derivatives may increase

cholesterol excretion into the bile, leading to cholelithiasis. Fenofibrate should be discontinued if gallstones are found. Pancreatitis, elevations in serum transaminases, chronic active hepatitis, and cholestatic hepatitis have been associated with fenofibrate therapy. Cirrhosis has been reported in rare cases in association with chronic active hepatitis. Mild to moderate decreases in hemoglobin, hematocrit, and white blood cell counts have been observed in patients following initiation of fenofibrate therapy, but levels generally stabilize as therapy continues. However, there have been rare reports of thrombocytopenia and agranulocytosis.82 Myopathy Risk. Q39.9 Fibrate monotherapy has occasionally been associated with myopathy, and rarely with rhabdomyolysis,

None listed

Warnings & Precautionsa Malignancies

Hematologic

Controversial data concerning malignancy risk (incl. BCC)

Mild to moderate anemia, leukopenia, thrombocytopenia aVenous thromboembolism with fenofibrate

Hepatobiliary aMay

cause cholelithiasis fibrates risk hepatocellular drug-induced liver injury

aBoth

Renal aRare

myopathy/rhabdomyolysis (avoid statin/gemfibrozil) aMonitor renal function in patients with renal insufficiency

Metabolic Paradoxical, severe, reversible ↓ Hgb A1C

Miscellaneous May ↑ noncardiovascular mortality (gemfibrozil)

Pregnancy Prescribing Status Traditional US Food and Drug Administration rating—category C aUnder “Warnings

Newer ratingb—Moderate-high risk

& Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid. bSee Chapter 65, Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings. BCC, Basal cell carcinoma; Hgb, hemoglobin. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https:// www.wolterskluwercdi.com/facts-comparisons-online/).

CHAPTER 39

TABLE Selection of Lipid-Lowering Drug According To 39.6 Type of Hyperlipidemia

Type of Dyslipidemia

Therapeutic Recommendation

Hypercholesterolemia alone

Statin Statin and ezetimibe Statin and a resin (the dose of resin clarithromycin >> azithromycin

Combined strong CYP3A4 inhibitors and p-glycoprotein inhibitors ↑ colchicine serum levels, toxicity

Azoles/triazoles

Ketoconazole > itraconazole >> fluconazole (only doses >200 mg)

same

Calcium-channel blockers

Diltiazem, verapamil

same

Calcineurin inhibitors

Cyclosporine, tacrolimus (oral)

same

Foods

Grapefruit juice

same

Inotropic agents

Digoxin

May ↑ colchicine serum levels, uncertain mechanism

HIV meds

Fosamprenavir

same

Vitamins

Cyanocobalamin (B12)

Colchicine may ↓ serum concentrations cyanocobalamin and folate (also fat soluble vitamins A, D, E)

Minerals

Iron

Colchicine may ↓ serum concentration of iron, risk anemia

Lower-Risk Drug Interactions

aOverall

highest-risk drug interactions indicated in bold italics. CYP, Cytochrome P-450; HIV, human immunodeficiency virus. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: a Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. (http://www.hanstenandhorn.com/).

shock.39,72 Respiratory distress syndrome, disseminated intravascular coagulation, and bone marrow failure may ensue. Other toxic manifestations include hepatic failure and late central nervous system (CNS) disorders. Myopathy, hypocalcemia, alopecia, stomatitis, and porphyria cutanea tarda have been reported in acutely intoxicated patients, who ultimately survived.39,72 Chronic intoxication may uncommonly occur after prolonged therapy with at least 1 mg daily. Complications include leukopenia, aplastic anemia, myopathy, and alopecia. Azoospermia and megaloblastic anemia, secondary to vitamin B12 malabsorption, have also been described.39 Treatment is supportive.73 Intravenous colchicine carries serious risk, including death and is no longer available in the United States.41 Use in Pregnancy and Lactation. In otherwise healthy women, colchicine use during pregnancy has been associated with lower birthweight and lower gestational age.74 It is classified as pregnancy Category C. However, to prevent disease relapse in women with FMF and Behçet, the literature strongly supports the ongoing use of colchicine throughout pregnancy. In these settings, studies have shown no increase in fetal malformations or miscarriages.74,75 The American Academy of Pediatrics classifies colchicine as compatible with breastfeeding, in which case it should be taken immediately after nursing.76 Monitoring Guidelines. Monitoring should be individualized with special consideration for overall health status and coadministered medications. Complete blood counts (CBC), platelet count,

serum multiphasic analysis, and urinalysis should be performed at least every 3 months.51 Monthly laboratory monitoring for the first few months of therapy is reasonable.

Fumaric Acid Esters Fumaric acid esters (FAE) have been used for the treatment of psoriasis for decades. Used primarily in Europe, especially Germany, the medication is not currently available in the United States. The oral preparations used are usually mixtures of esters. It is unclear whether there is a single active component within these mixtures or whether additive or synergistic effects are at work.77 FAE appear to be modestly active against psoriasis in controlled studies, with fewer serious AE than many other medications used to treat this disease. Commonly reported AE include flushing and GI problems. More severe AE are reported less commonly.78

Niacinamide Pharmacology Nicotinic acid (niacin, vitamin B3) is an essential dietary constituent, the deficiency of which leads to pellagra. In the body, nicotinic acid (niacin) is converted to niacinamide (nicotinamide), which functions as a crucial coenzyme that accepts hydrogen ions in oxidation-reduction reactions essential for tissue respiration; it is a necessary cofactor for adenosine triphosphate (ATP)

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production.79 Both nicotinic acid and niacinamide are readily absorbed from the GI tract and distributed to all tissues. Mechanism of Action. Q40.7 Several mechanisms have been proposed to explain the anti-inflammatory effect of niacinamide. Niacinamide inhibits poly-(adenosine) diphosphate-ribose polymerase-1 (PARP-1), a nuclear enzyme that enhances nuclear factor-κB transcription. Inhibition of this pathway alters leukocyte chemotaxis by dysregulation of adhesion factors necessary for migration.80 Niacinamide reduces lysosomal enzyme release and stabilizes leukocytes by inhibiting cyclic adenosine monophosphate phosphodiesterase (cAMP PDE), and also inhibits lymphocytic transformation and the production of antibodies. This latter mechanism makes the drug particularly useful for the treatment of antibody-mediated diseases (e.g., bullous pemphigoid).80 Other reports show niacinamide to be effective in inhibiting mast cell degranulation, thereby preventing the release of vasoactive amines, such as histamine and eosinophil chemotactic factor, and providing yet another useful mechanism for the treatment of bullous pemphigoid.81 Topical niacinamide retains these anti-inflammatory effects, making it a potentially useful adjunct treatment for acne. It also stabilizes epidermal barrier function through a reduction in transepidermal water loss, increases protein (e.g., keratin) and ceramide production in the stratum corneum, speeds up keratinocyte differentiation, and inhibits the transfer of melanosomes from melanocytes to keratinocytes, all of which make it an attractive topical therapy to fight the cutaneous signs of aging.82,83 More recently, niacinamide has been shown to possess chemoprevention properties. Specifically by preventing ATP depletion and glycolytic blockade, niacinamide promotes DNA repair and reduces immunosuppression caused by UV radiation.84

Clinical Use Off-Label Dermatologic Uses Overall Dermatologic Uses. Niacinamide can be used for pro-

phylaxis and treatment of pellagra caused by poor nutrition, Hartnup disease, or carcinoid tumors.79 Of most interest, however, is niacinamide’s reported utility in treating autoimmune bullous dermatoses, including the full spectrum of pemphigoid,81,85,86 pemphigus,87,88 dermatitis herpetiformis,89 and linear IgA dermatosis.87 Anecdotally, it has also been used to treat erythema elevatum diutinum,90 polymorphous light eruption,91 granuloma annulare,92 and necrobiosis lipoidica.93 Systemic niacinamide, in combination with azelaic acid, folic acid, copper, and pyridoxine, has also been marketed as a prescription dietary supplement, useful in the management of acne vulgaris. Purported uses for topical niacinamide include improved epidermal barrier function and keratinocyte differentiation to fight signs of aging, improvement of isoniazid-induced pellagra-like skin lesions, improvement in wound healing, and anti-inflammatory and sebosuppressive effects useful in the treatment of acne vulgaris and rosacea.82 Topical niacinamide has also been shown to reduce the immunosuppressive effects of UV irradiation, making it an attractive additive in topical sunscreen preparations.94 Similarly, by reducing cutaneous immunosuppression, impeding cellular energy depletion, and promoting DNA repair, oral niacinamide has found a niche as a chemopreventive agent for nonmelanoma skin cancers.84 Bullous Dermatoses. One randomized, open-label trial suggested comparable efficacy and fewer AE using the combination of niacinamide and tetracycline, compared with prednisone as

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first-line therapy for bullous pemphigoid.85 Another small review suggested that the combination of niacinamide and tetracycline derivatives may be an effective alternative to CS in pemphigus foliaceus and pemphigus erythematosus and a CS-sparing adjuvant, rather than CS alternative in pemphigus vulgaris.87A more recent retrospective review of 51 patients with a spectrum of pemphigus also concluded that this combination therapy may be useful as ‘CS-sparing-sparing therapy’.95 Assessment of clinical response to niacinamide alone, in treating autoimmune blistering disorders and erythema elevatum diutinum, has clearly been complicated by concomitant tetracycline or erythromycin use in these studies. It has been proposed that the anti-inflammatory properties of these antibacterial agents may function synergistically with niacinamide in the treatment of diseases with excessive PMN chemotaxis.81,85 Because tetracycline alone has been reported to clear bullous pemphigoid, it is difficult to assess niacinamide’s exact contribution in treatment of bullous diseases.96 However, one case of localized bullous pemphigoid responding to niacinamide alone has been reported.97 Skin-Cancer Chemoprevention. In a double-blind, randomized, controlled trial of 386 immunocompetent participants at high risk for skin cancer, niacinamide reduced rates of new basal cell carcinomas by 20% and new squamous cell carcinomas by 30%.84 Research suggests niacinamide might serve a similar role in preventing arsenic-induced skin cancers.98 Although more studies are warranted, enthusiasm exists for the chemopreventive use of nicotinamide in patients at high risk for skin cancer, particularly in the setting of renal transplantation.99,100 Photodermatoses. Some researchers believe that niacinamide has a beneficial effect in the prevention of polymorphous light eruption.91 However, using phototesting, others failed to document this favorable response.101 Dosing Strategies. In the treatment of autoimmune bullous diseases81,85 and granulomatous diseases,92,93 the dose of niacinamide has averaged 500 mg, 3 times daily. Four times daily dosing may also be considered. The concurrent tetracycline dose has typically been 500 mg, 4 times daily, although lower doses have proved to be efficacious. Minocycline 100 mg twice daily has been substituted in patients with GI distress attributed to tetracycline.81,85 There is also significant clinical experience combining niacinamide with doxycycline 100 mg twice daily.95 For chemoprevention purposes, the studied dose of niacinamide has been 500 mg twice daily.84 Adverse Effects. Niacinamide is considered a very safe medication with few AE. Box 40.3 outlines the drug risks profile for niacinamide. Extensive information regarding AE is available through the older literature on schizophrenia, for which the drug was used in doses of 3 to 12 g daily. Headache and GI complaints occasionally occur. Hepatotoxicity is considered extremely rare but may justify the monitoring of liver function tests in patients receiving long-term, high-dose therapy.102 Whereas nicotinic acid (niacin) is a potent vasodilator, niacinamide is not, and thus is not typically associated with flushing and other prostaglandin-triggered AE.102 Monitoring Guidelines. Whereas nicotinic acid (niacin) adversely affects glucose tolerance curves, niacinamide (nicotinamide) does not typically have the same effect. Diabetic patients should perhaps still be monitored.102 Nicotinic acid may increase the risk of myopathy when used with other lipid-lowering agents. Although a similar risk has yet to be reported for niacinamide, close observation may be warranted.103

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• BOX 40.3 Drug Risks Profile—Niacinamide Contraindications Hypersensitivity to niacinamide or components of formulation

“Not for OTC use” in gallbladder disease, hx jaundice/ liver disease, diabetes, gout, or peptic ulcer

TABLE Nonsteroidal Anti-inflammatory Drugs 40.5 Categories and Examples

Category

Indole/indene acetic acids

Etodolac Indomethacin Sulindac

Lodine Indocin Clinoril

Heteroarylacetic acids

Diclofenac Ketorolac Tolmetin

Voltaren Toradol Tolectin

Arylpropionic acids

Fenoprofen Flurbiprofen Ibuprofen Ketoprofen Naproxen Oxaprozin

Nalfon Ansaid Motrin, Advil Oruvail Naprosyn, Alleve Daypro

Anthranilic acids (fenamates)

Meclofenamate Mefenamic acid

Mylan Ponstel

Enolic acids (oxicams)

Meloxicam Piroxicam

Mobic Feldene

Phenylbutazonea

Butazolidin

Nabumetone

Relafen

Celecoxib Rofecoxiba Valdecoxiba

Celebrex Vioxx Bextraa

None listed None listed

Pregnancy Prescribing Status Traditional US Food and Drug Administration rating—unrated

Newer ratingb —compatible

aUnder “Warnings

& Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid. bSee Chapter 65, Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings. OTC, Over the counter. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https:// www.wolterskluwercdi.com/facts-comparisons-online/).

Nonsteroidal Anti-inflammatory Drugs For additional information, nonsteroidal anti-inflammatory drugs (NSAID) are also discussed in Chapter 33.

(pyrazolidinediones) Alkanones

Selective COX-2 Inhibitors

Pharmacology NSAID are compounds with a substituted phenolic or benzene ring that inhibit cyclo-oxygenase (COX) or lipoxygenase transformations of arachidonic acid. Such inhibition disrupts the production of prostaglandins and leukotrienes, which mediate inflammation.104 These drugs have a wide spectrum of use in dermatology. The most common NSAID and their respective categories are listed in Table 40.5.

Clinical Use Off-Label Dermatologic Uses Erythema Nodosum. Aspirin has been used in the treatment

of erythema nodosum, although reports suggest that indomethacin may be a better drug for this problem.105,106 Naproxen has also been shown to be efficacious.107 Sweet Syndrome. Indomethacin has been proved effective first-line therapy for Sweet syndrome, with 17 of 18 patients in an open, nonrandomized trial responding.108 Indomethacin is typically given as 100 to 150 mg daily in divided doses. Acne Vulgaris. Although not commonly used, NSAID have been shown to be helpful in the treatment of acne vulgaris. In one double-blind study the combination of ibuprofen and tetracycline proved statistically superior to either drug alone and placebo in the treatment of moderately severe acne.109 Erythromelalgia and Related Conditions. Aspirin has been shown to be effective therapy for erythromelalgia.110 Although therapeutic failures have been reported, a single daily dose of aspirin is said to result in a dramatic relief of symptoms for some patients.111,112 Relief obtained from aspirin is reported to last for

Trade Names

Nonselective COX-1 and COX-2 Inhibitors

Boxed Warnings Warnings & Precautionsa

Examples

aNo

longer marketed in the United States.

COX, Cyclo-oxygensase. From Brunton LL, Lazo JS, Parker KL (Editors). Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th ed. New York: McGraw-Hill; 2006;675–680.

days. In comparison, improvement from indomethacin is reported to last for less than 24 hours. This difference is attributed to aspirin’s irreversible inactivation of platelet cyclo-oxygenase, compared with indomethacin’s reversible inhibition of this enzyme.110 The acral ischemic complications seen in thrombocythemia vera and thrombocythemia associated with polycythemia vera respond to aspirin therapy.113 Vascular Malformations and Tufted Angioma. Aspirin may reduce pain and soft tissue swelling associated with venous malformations and decrease stroke-like episodes in Sturge-Weber syndrome.114,115In addition, low-dose aspirin has been shown to decrease the redness, bulk and tenderness of tufted angiomas, with and without associated platelet-trapping syndrome in children.116–118 Although low-dose aspirin at 3 to 5 mg/ kg/day has not been associated with Reye syndrome, therapy should be held for predisposing suspected varicella or influenza infections.117 Niacin-Induced Cutaneous Reactions. Aspirin 325 mg suppresses the flushing, itching, warmth and tingling triggered by niacin therapy.119 Pruritus Secondary To Systemic Diseases. Although indomethacin has been reported to help relieve the pruritus of late-stage

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human immunodeficiency virus (HIV)-1 infection,120 NSAID are typically ineffective in alleviating the pruritus associated with common dermatoses.121 In contrast, pruritus of polycythemia vera, a disease characterized by an increased number of skin mast cells, is often responsive to aspirin therapy, which directly suppresses mast cell prostaglandin metabolism.122 Mastocytosis. Systemic mastocytosis may also be managed best with the cautious addition of aspirin after first initiating adequate H1- and H2-antihistamine blockade therapy. Aspirin effectively inhibits the formation of prostaglandin D2, an important mediator of systemic mastocytosis. The institution of aspirin therapy should be carried out with extreme caution, because severe hypotensive episodes culminating in death have been described.123 Lower doses of aspirin than previously used may prove adequate.124 Urticaria and Urticarial Vasculitis. NSAID have been used with some benefit in treating several types of urticaria. The combination of the NSAID nimesulide and the mast cell degranulation inhibitor ketotifen has proved effective in a variety of physical urticarias.125 Aspirin has been beneficial in nonimmunologic contact urticaria.126 Aspirin, indomethacin, and ibuprofen all may improve delayed pressure urticaria.127 Aspirin has also been used to carefully desensitize patients with aspirin-induced urticaria and angioedema.128 Indomethacin was found to be helpful in conjunction with heat desensitization for localized heat-induced urticaria.129 Finally, indomethacin has been shown to be a therapeutic option in urticarial vasculitis.130 Ultraviolet-Induced Erythema. A role for NSAID in minimizing sunburn potential has been investigated. Significant, but incomplete, suppression of ultraviolet B (UVB) erythema has been documented with aspirin, as well as with oral and topical indomethacin.131,132 Topical indomethacin has also been shown to suppress UVA-induced and psoralens plus UVA (PUVA)-induced inflammation.132 One study documented suppression of both erythema and proliferative cell nuclear antigen in a subset of patients receiving oral celecoxib, before sunlight-simulated UV radiation. Notably, only half the patients in this study were responders, suggesting a need to identify this subset of individuals that might benefit from such therapy.133 Finally, pain relief and a reduction in erythema, following superficial natural sunburn has been documented in a randomized, double-blind study using diclofenac sodium 0.1% gel.134 Chemoprevention of Malignancy. Q40.8 NSAID are believed to effect cutaneous carcinogenesis by both COX-dependent and -independent pathways; their antineoplastic role is an evolving field.135 COX, particularly COX-2 is upregulated in UVB-irradiated human keratinocytes, as well as human squamous cell carcinomas.136,137 In multiple studies of hairless mice, both COX-2 selective and nonselective NSAID inhibited UVinduced skin tumor production, likely attributable to their ability to reduce PGE2, which induces COX-2 expression in keratinocytes.137–140 Meta-analyses and population-based studies of NSAID and aspirin use in humans suggest that these drugs may reduce the risk of nonmelanoma skin cancer, particularly squamous cell carcinoma and potentially basal cell carcinoma, particularly in high risk individuals.141–145 Further studies are warranted; however, they will likely not include currently available oral selective COX-2 inhibitors, given their increased risk of cardiovascular events.135

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Topical 3% diclofenac, a potent inhibitor of inducible COX2, in 2.5% hyaluronic acid, is FDA approved for the treatment of actinic keratoses.146 This gel is applied twice a day for 60 to 90 days, with efficacy similar to that of topical 5-fluorouracil. Overall, this gel formulation is well tolerated, with application site erythema being the most common AE.147 Diclofenac gel has proved safe and may be useful in preventing invasive squamous cell carcinoma in organ transplant patients.148 In one study, the progression of disseminated superficial actinic porokeratosis was reduced with this drug.149 With regard to melanoma, a number of studies suggest that long-term aspirin use may be associated with decreased risk of melanoma, especially in women.150 However, contradictory studies do exist, including one that demonstrated increased melanoma risk in women and another that demonstrated increased risk in men.151,152 Interestingly, one retrospective study, of 1522 patients diagnosed with melanoma, demonstrated a survival advantage in patients taking aspirin, as well as earlier stage diagnosis in patients already on aspirin. The authors suggested that these benefits may result not only from aspirin’s inhibition of tumor-derived prostaglandin production, but its inhibition of platelets, which have been shown to aid in cancer metastasis.153 In another small study, the Breslow depth at time of melanoma diagnosis was reduced in aspirin users versus nonusers.154 Clearly, additional studies are warranted. Adverse Effects. Within the realm of dermatology, NSAID are perhaps better known for their cutaneous adverse reactions, rather than for their clinical utility in treatment of the aforementioned dermatoses. There are several complete reviews on this subject.155–157 Cutaneous drug reactions commonly induced by NSAID include potentially serious entities, such as StevensJohnson syndrome, toxic epidermal necrolysis, and anaphylactoid reactions. Box 40.4 drug risks profile provides more detailed information.

Penicillamine Penicillamine is a breakdown product of penicillin. It is a potent chelator of heavy metals (i.e., copper, gold, lead, mercury, and zinc), promoting their excretion in urine. Nondermatologic indications for the drug’s use include the treatment of heavy metal poisoning, cystinuria, Wilson disease, primary biliary cirrhosis, and rheumatoid arthritis. Dermatologists have historically used penicillamine primarily for the treatment of various forms of progressive systemic sclerosis (PSS), primarily for localized versions of the condition. Its use seems to be declining, undoubtedly because of its long list of common AE, its dubious track record of efficacy, and the availability of more reliable therapeutic options. In fact, the practicing dermatologist is probably more likely to encounter cutaneous eruptions induced by penicillamine than to prescribe this medication.

Pharmacology See Table 40.2 for key pharmacologic concepts of penicillamine. The oral absorption of penicillamine ranges between 40% and 70% and is diminished by food and antacids containing magnesium-aluminum salts. In addition, the absorption is diminished in patients with GI manifestations of PSS. The peak plasma concentration of the parent compound occurs within 1 to 3 hours after a dose; its half-life also approximates 1 to 3 hours.158 Hepatic

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Increased risk of serious GI events bleeding, ulceration, perforation

months, with time to response and remission varying widely. The dose should be weaned as possible, while maintaining remission. Using such a regimen, Jimenez and Sigal160 reported a cutaneous response rate of over 90% in a 15-year prospective study of the use of penicillamine in PSS. Contraindications. Dose adjustments and extra caution should be used in those allergic to penicillin or with renal dysfunction, during pregnancy, and in the pediatric population. There is a relative contraindication to penicillamine therapy in patients simultaneously undergoing therapy with gold, phenylbutazone, oxyphenbutazone, antimalarial agents, or cytotoxic agents.

Hypersensitivity Reactions

Hematologic

Adverse Effects General Effects. Common AE of therapy include nausea,

aSJS/TEN, exfoliative

aReduced

• BOX 40.4 Drug Risks Profile—Nonsteroidal Anti-

inflammatory Drugs Contraindications Hypersensitivity to NSAID or components formulations Hx of urticarial, asthma, or other allergic rxn to ASA, NSAID

Avoid use in setting of CABG surgery Celecoxib use in sulfa-allergic patients (controversial)

Boxed Warnings Increased risk of cardiovascular thrombotic events; MI, CVA

Warnings & Precautionsa dermatitis aSerum-sickness like reaction with piroxicam

platelet function/aggregation with bleeding, possibly anemia

Renal

Hepatic

aReduced

aTransaminase

renal function—greatest risk CKD, dehydration, elderly, diuretics, ACE inhibitors, CHF, hepatic impairment Hyperkalemia commonly associated (esp. elderly, diabetics)

elevations can occur, monitor closely Rare fulminant hepatitis, liver failure reported

Neurologic Aseptic meningitis, at risk SLE or MCTD patients

Pregnancy Prescribing Status Traditional US Food and Drug Administration rating—category C and D (varies timing, rx)

Newer ratingb —Moderate-High Risk

aUnder “Warnings

& Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid. bSee Chapter 65, Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings. ACE, Angiotensin converting enzyme; ASA, acetylsalicylic acid; CABG, coronary artery bypass graft; CVA, cerebrovascular accident; CHF, congestive heart failure; CKD, chronic kidney disease; GI, gastrointestinal; MCTD, mixed connective tissue disease; MI, myocardial infarction; SLE, systemic lupus erythematosus; SJS/TEN, Stevens-Johnson syndrome/toxic epidermal necrolysis. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https:// www.wolterskluwercdi.com/facts-comparisons-online/).

metabolism occurs, transforming most penicillamine to disulfides and inorganic sulfate. The disulfides play major roles in both therapeutic and toxic effects. The disulfide products readily bind to plasma proteins and are not excreted renally. These metabolic products accumulate during the first few weeks of therapy and are slowly eliminated once therapy is stopped. Unmetabolized drug is primarily eliminated via the kidneys, with unabsorbed drug found in the feces. Mechanism of Action. The binding of penicillamine to copper has been used in patients with Menkes syndrome, being simultaneously treated with intramuscular copper. A different mechanism of action, inhibition of collagen maturation, appears to be at work in the treatment of PSS.159

Clinical Use Off-Label Dermatologic Uses. In most cases of PSS, adult dosing is initiated at 125 to 250 mg daily, with increases of 125 to 250 mg daily, occurring incrementally, every 1 to 3 months, until satisfactory remission or toxicity occurs (usually at levels between 750 and 1500 mg daily). Therapy is commonly required for several

vomiting, abdominal pain, and diarrhea. The list of noncutaneous AE reported with the use of penicillamine is exhaustive. Among other unpleasant possibilities, the clinician must be aware of the possibility of proteinuria, blood and platelet dyscrasias, and hepatotoxicity. Bialy-Golan and Brenner161 included a thorough discussion of this topic in their review. Mucocutaneous Effects. Q40.9 Established adverse cutaneous effects related to the use of penicillamine are well known to anyone ever having the pleasure of taking a dermatology board examination. The adverse cutaneous effects include the bullous dermatoses (including several forms of pemphigus, cicatricial and bullous pemphigoid, and epidermolysis bullosa acquisita), a lupuslike syndrome, lichen planus, elastosis perforans serpiginosa, and pseudoxanthoma elasticum. More rarely described AE with penicillamine use include characteristic nail changes, a unique dermatopathy, and a Goodpasture-like syndrome.

Potassium Iodide In the physician’s armamentarium since the mid-1800s, potassium iodide was originally used for ailments, such as syphilis, lupus vulgaris, eczema, and psoriasis. Although more targeted medications are now used for these diseases, potassium iodide remains useful for treating cutaneous sporotrichosis, erythema nodosum, and several other dermatologic conditions.162,163

Pharmacology Mechanism of Action. Potassium iodide has no in vitro effect on Sporothrix schenckii. Rather, its efficacy is probably mediated through alteration in the host’s immunologic or nonimmunologic response to the organism. Iodides concentrate in infected granulomas and necrotic tissue and have been shown to inhibit further granuloma formation.163 Schulz and Whiting162 speculated that the mechanism of action of potassium iodide in hypersensitivity disorders, such as erythema nodosum, is the result of an immunosuppressive effect mediated through heparin. Heparin, which is released in large quantities from mast cells by iodide administration, has been shown to suppress delayed hypersensitivity reactions.163 Potassium iodide can also suppress the generation of inflammatory oxygen intermediates from activated PMN, and may thus confer protection from autooxidative tissue injury.162

Clinical Use Box 40.5162–174 lists indications and contraindications for potassium iodide.

CHAPTER 40

• BOX 40.5 Potassium Iodide Indications and

Contraindications162–174 US Food and Drug Administration-Approved Indications None Specific to Dermatology

Other Dermatologic Uses Fungal Infections Sporotrichosis163–166 Panniculitis Erythema nodosum162,167 Nodular vasculitis/erythema induratum162,167 Subacute nodular migratory panniculitis168

Hypersensitivity Reactions Erythema multiforme167 Sweet syndrome169,170 Pyoderma gangrenosum171 Granulomatous Dermatoses Wegener granulomatosis172 Granuloma annulare173,174

Contraindications Absolute Hypersensitivity to iodides

Relative Hypothyroidism Cardiac disease Renal insufficiency Addison disease Hyperkalemiaa Pregnancy prescribing status—Category D aConcomitant

use of potassium iodide and potassium-sparing diuretics can result in hyperkalemia.

Off-Label Dermatologic Uses Sporotrichosis. Although oral itraconazole has largely sup-

planted its use, potassium iodide remains an effective agent for lymphocutaneous sporotrichosis. In a single case, sporotrichosis responded to potassium iodide therapy after itraconazole therapy had failed.164 Potassium iodide has also been reported to clear subcutaneous mucormycosis.165 The initial dose for sporotrichosis is 5 drops of the saturated solution (each drop contains 67 mg of potassium iodide) 3 times daily in milk or juice. This dose is gradually increased by 3 to 5 drops (with roughly weekly increments), until a dose of at least 15 drops, 3 times daily is reached. Doses up to 50 drops, 3 times daily may be required. Lesions usually heal within 2 to 4 weeks, and therapy is continued for an additional 2 to 4 weeks.166 Compliance may be increased with once-daily dosing, which proved to be as safe and efficacious, as split dosing in one randomized nonblinded study.168 Panniculitis. Reports of excellent results with potassium iodide in subacute nodular migratory panniculitis168 prompted Schulz and Whiting to use this drug for erythema nodosum and nodular vasculitis.162 Of their 45 patients, 40 responded; symptoms were relieved within 2 days, and lesion resolution occurred in an average of 2 weeks. Subsequent uncontrolled studies supported the beneficial role of potassium iodide therapy in these diseases.162,167 Clinical response tended to be better in those who received treatment, shortly after the onset of their disease. Improvement was most dramatic in patients with systemic symptoms, such as fever and joint pains.169 Doses ranged from 360 to 900 mg daily; most patients received 900 mg daily. Other Dermatoses. Potassium iodide has been used for treatment of erythema multiforme, Sweet syndrome, and PG. Although their studies were uncontrolled, advocates reported prompt and dramatic improvement correlating with initiation of therapy.169–171 Potassium iodide was also used with prednisolone to successfully treat a single patient with a limited form of

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granulomatous polyangiitis (Wegener granulomatosis).172 Treatment of granuloma annulare with potassium iodide is controversial, with a few reports of improvement after months of therapy; one double-blind report, however, showed no significant advantage over placebo.173,174 Adverse Effects. Overall, potassium iodide therapy is considered quite safe. Adverse reactions are usually associated with chronic therapy and are dose-related. Hypothyroidism. Q40.10 Iodide goiter, with or without hypothyroidism, may occasionally be induced by high-dose, long-term potassium iodide therapy. Patients typically have an underlying thyroid disease. In these patients, there is impairment of the autoregulatory mechanism required to escape from the Wolff-Chaikoff effect (i.e., cessation of thyroid hormone synthesis caused by excess iodide, inhibiting organic binding of iodide in the thyroid gland).175 Other Systemic Adverse Effects. Chronic intoxication begins with an unpleasant brassy taste, a burning sensation in the mouth, and increased salivation. Coryza, sneezing, and eye irritation are common. Mild iodism simulates a head cold. Parotid and submaxillary glands may become enlarged and tender. Gastric irritation is common. Diarrhea, fever, anorexia, and depression may occur.176 Vasculitic syndromes have been reported.177 Cutaneous Adverse Effects. Q40.11 Skin lesions of various morphologies are remarkably common and include acneiform, dermatitic, and vascular eruptions.162,176,177 A distinctive, vegetating eruption known as iododerma may occur with chronic lowdose ingestion. Also, iododerma has been reported after one large dose of iodide radiocontrast dye in the setting of impaired kidney function.178 Paradoxically, iodide ingestion has been implicated in triggering erythema multiforme and erythema nodosum, as well as flaring PG. Flares of dermatitis herpetiformis and pustular psoriasis, as well as the development of bullous pemphigoid, have also been reported.179,180 Monitoring Guidelines. Q40.10 Before initiating potassium iodide therapy, patients should be questioned regarding previous history of thyroid disease and thyroid gland size should be assessed. Note should be taken of concurrent medications, such as lithium and amiodarone, that can also affect thyroid function. Baseline thyroid-stimulating hormone (TSH), thyroxine (T4) level, antithyroglobulin, and antimicrosomal antibodies should be checked in patients suspected of having an underlying thyroid disease.175 Within several weeks of potassium iodide initiation, the autoregulatory mechanism of a normal thyroid gland should allow escape from the Wolff-Chaikoff effect, and so a TSH should be drawn on all patients 1 month after initiation of therapy.175 Repeat TSH values should be ordered at least yearly. Iodideinduced hypothyroidism is typically reversible with discontinuation of therapy.173,175 If the potassium iodide therapy induces hypothyroidism, yet the drug is both effective and deemed important to continue, thyroid replacement therapy is a relatively simple therapeutic option (see also Chapter 39). Finally, large doses should not be given to pregnant women because iodide goiter and hypothyroidism are commonly induced in the fetus.173

Thalidomide Arguably no pharmacologic agent in recent history has been vilified to the extent of thalidomide (Fig. 40.2). Thalidomide was introduced to Western Europe in the late 1950s as a ‘safe’ sleeping aid with negligible AE. (The drug never obtained approval from

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O

O

N N O

• Fig. 40.2

O

H

Thalidomide structure.

the FDA at that time, and did not enter the mainstream American market until 1998.) Dramatic reports soon began to appear of an association between use of thalidomide during pregnancy and limb defects in infants (phocomelia), often accompanied by internal deformities. In 1961 the drug was rapidly withdrawn from world markets as its teratogenicity was confirmed, and its ability to cause irreversible peripheral nerve damage became apparent. Unfortunately, before its disappearance, thalidomide-related cases of phocomelia were estimated in the thousands. The world’s shock on viewing those afflicted sparked a renewed vigilance with regard to drug safety issues. The word thalidomide became symbolic of our former naiveté. Thalidomide’s exile proved short-lived. In 1965 it was reported to dramatically alleviate the symptoms associated with erythema nodosum leprosum (ENL). Shortly thereafter, clinical researchers began reporting its beneficial effects for a variety of conditions; its use was limited to a ‘named patient’ basis. In 1998 the FDA granted thalidomide approved status for the treatment of ENL, opening the door for its use in off-label indications. Although the rehabilitation of the drug’s image is well under way, its probation in the public’s mind continues. Those electing to prescribe thalidomide must be mindful of its potential hazards and ever respectful of those whose lives have been irrevocably altered by this medication.

Pharmacology Table 40.2 lists key pharmacologic concepts for thalidomide and other systemic drugs. Structure. Thalidomide is a nonpolar glutamic acid derivative, specifically, an N-phthalimidoglutarimide. Being a piperidinedione hypnotic, it is structurally similar to glutethimide, methyprylon, and bemegride. The drug consists of a left-sided phthalimide ring and a right-sided glutaramide ring, with a single asymmetric carbon atom centrally; this feature allows for its rapid conversion between two isomeric forms in vivo (see Fig. 40.2).181,182 Absorption and Bioavailability. Thalidomide is available for oral administration only. There is little difference in absorption, whether taken with or without meals. Because thalidomide displays poor solubility in water and there is no intravenous formulation, the absolute bioavailability of thalidomide in humans has not been calculated. Animal studies yielded values ranging from 67% to 93%.183 The drug is absorbed relatively slowly, reaching peak plasma levels usually within 2 to 6 hours.183 Its onset of action varies according to the condition being treated (see Clinical Use section). A volume of distribution of 120 L has been estimated.183 Protein-binding studies have not been performed in humans. Given thalidomide’s nonpolar nature, however, protein binding in the plasma is speculated to be significant. Even so, thalidomide readily crosses the placental membrane, owing to the drug’s lipid solubility. Metabolism and Excretion. Studies regarding the human metabolism continue. In animal studies, the major degradative

pathway appears to be nonenzymatic hydrolysis. At physiologic pH, thalidomide undergoes rapid hydrolytic degradation into most of its 12 theoretically possible cleavage products. There is also evidence that hepatic metabolism of the parent compound involves the CYP 2C subfamily.184 The half-life of thalidomide has been determined to be approximately 9 hours. Its excretion appears to be predominantly nonrenal, with less than 1% of a dose found unchanged in the urine after 24 hours. The total body clearance of the drug was calculated to be approximately 10 L per hour.183,185 Mechanism of Action. Table 40.3 lists drug mechanisms and clinical correlates for thalidomide. Very few of the multiple biologic activities attributed to thalidomide have been explained at the molecular level. For such a simple molecule, it exerts myriad effects. The task of sorting out how the drug works is in no small way complicated by its 12 cleavage products. Most of the known mechanisms of action can be included under one of the following headings: 1. Hypnosedative effects; 2. Immunomodulatory and anti-inflammatory effects; and 3. Neural and vascular tissue effects. Hypnosedative Effects. Thalidomide readily penetrates the CNS, where it exerts hypnosedative effects comparable with those of barbiturates. Despite similar potencies even at large doses, acute toxicity is rare. Thalidomide acts via a still-undetermined mechanism, independent of that of the barbiturates. It is thought that this sedating property may in part explain thalidomide’s effectiveness in the treatment of pruritic conditions, such as prurigo nodularis (PN) and actinic prurigo. Immunomodulatory and Anti-inflammatory Effects. Multiple studies, some yielding contradictory results, have focused on thalidomide’s influence on the immune system. Q40.12 The drug exhibits specific inhibition of TNF-α.186 When given to healthy volunteers, the drug induced a drop in their helper T-cell counts and a corresponding, although relatively small, rise in their suppressor T-cell number.187 The drug has been observed to potently suppress the production of IL-12, which plays a crucial role in the development of cellular immune responses.188 Disease-specific influences of these molecular effects remain to be worked out. However, these studies provide insight into thalidomide’s possible modes of action in disorders characterized by undesirable cellular immune reactions, such as ENL, sarcoidosis, and chronic graft-versus-host disease (GVHD). Humoral immunity is also affected, as evidenced by the selective enhanced production of IL-4 and IL-5 (B-cell activators) with simultaneous IFN-γ inhibition.189 Paradoxically, both enhanced and diminished humoral responses have been experimentally observed with thalidomide administration. Thalidomide’s success in treating other diseases, such as chronic cutaneous lupus erythematosus (CCLE) and PG, can perhaps best be understood by examining its anti-inflammatory properties. Thalidomide has been shown to reduce PMN chemotaxis and phagocytosis.190,191 Monocyte phagocytosis is also decreased.192 In addition, antagonism of inflammatory mediators, such as histamine, acetylcholine, prostaglandins, and 5-hydroxytryptamine (serotonin) has been demonstrated.190 Given these qualities, the drug might theoretically be expected to work for a great number of inflammatory disorders. Neural and Vascular Tissue Effects. It has been hypothesized that thalidomide has direct effects on nervous tissue. Whether the drug’s effectiveness in treating prurigo nodularis (PN) in one patient is mediated by the same mechanism that causes peripheral

CHAPTER 40

• BOX 40.6 Thalidomide Indications and

Contraindications181–206 US Food and Drug Administration-Approved Indications Erythema Nodosum Leprosuma193–196

Other Dermatologic Uses HIV-Related Dermatoses

Lymphocytic Infiltrates181

AIDS-associated oral stomatitisa197 AIDS-related Kaposi sarcoma198,199

Cutaneous features lupus erythematosus200–204 Jessner lymphocytic infiltrate of the skin Cutaneous lymphoid hyperplasia

Neutrophilic Dermatoses181 Giant aphthous stomatitis Behçet disease Pyoderma gangrenosum

Vesiculobullous Dermatoses181 Erosive lichen planus Bullous pemphigoid Cicatricial pemphigoid Recurrent erythema multiforme

Other Dermatoses181 Chronic graft-versus-host disease a,205

Prurigo nodularis/actinic prurigo206 Sarcoidosis Langerhans cell histiocytosis Weber-Christian disease Palmoplantar pustulosis Uremic pruritus Postherpetic neuralgia

Contraindications Absolute

Relative

Sensitivity to thalidomide Pregnancy Women of childbearing potential Patients with existing peripheral neuropathy Men engaging in sexual intercourse with women of childbearing potential

Patients with significant hepatic or renal impairment Patients with history of neuritis or other neurologic disorders Congestive heart failure or hypertension Constipation, other GI disorders Hypothyroidism

Pregnancy prescribing status—Category X aThalidomide

is generally considered the drug of choice for this disorder. AIDS, Acquired immunodeficiency syndrome; GI, gastrointestinal; HIV, human immunodeficiency virus.

neuropathy in another is still to be determined. Some evidence indicates that two distinct mechanisms may be at work, one leading to desirable, the other to undesirable, effects. For example, in cases of PN, abnormal or proliferating neural tissue seems to be preferentially affected. Definitive studies remain to be done. Multiple studies have demonstrated thalidomide’s ability to inhibit angiogenesis, a quality that has led to experimental use against various cancers. This effect may also contribute to its teratogenic potential.

Clinical Use Box 40.6181,193–206 lists indications and contraindications for thalidomide. US Food and Drug Administration-Approved Indication Erythema Nodosum Leprosum. Although no direct effect

against Mycobacterium leprae has been demonstrated, thalidomide is the drug of choice for ENL (type 2 leprosy reaction).190 This reaction occurs in approximately 50% of patients with lepromatous leprosy, but only occasionally in those with borderline forms. Over a decade after his initial work began the drug’s resurrection, Sheskin193 surveyed over 4500 cases of ENL, treated with

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thalidomide from around the world, and reported an amazing response rate of 99%. The drug is ineffective in reversal (type 1) leprosy reactions. For milder cases of ENL, thalidomide has been administered alone. In controlled studies, 100 mg was given 4 times daily for 7 days. The course was repeated for an additional 7 days for nonresponders and for relapses, which can be frequent.194,195 Others have successfully used an initial dose of 100 mg 3 to 4 times daily, with reduction to a 50 to 100-mg maintenance dose over 2 weeks.196 Attempts to discontinue the drug should be made periodically. Resolution of cutaneous ENL lesions almost uniformly begins within 24 to 48 hours. Systemic signs and symptoms of ENL tend to resolve within a few days as well. More severe cases of ENL, involving progressive neural degeneration, significant ocular involvement, or severe skin ulceration, require the combined use of thalidomide and CS. In general, antileprosy chemotherapy should continue throughout treatment of the leprosy reaction. Off-Label Dermatologic Uses—Well-Documented Benefits Lupus Erythematosus. Thalidomide has been successfully

used to treat the cutaneous manifestations of the various forms of lupus erythematosus (LE). The response rate in cutaneous lupus is impressive. A systematic review and meta-analysis of thalidomide for cutaneous LE demonstrated response rate of 90% (confidence interval [CI], 85–94), with over 60% achieving a complete response. The response rates were similar for patients starting at 50 mg/day as for those started at 100 mg/day. A review of studies that allowed direct comparison demonstrated no difference in response rates between CLE subtypes. Improvement is usually seen within 2 to 4 weeks.207 Thereafter, the dose may be tapered, with a maintenance dose requirement of 25 to 50 mg daily required for most patients.200 In patients withdrawn from the drug, the relapse rate was 71% (CI, 65–77). Those treated with a maintenance dose relapsed at a rate of 35% (CI, 25–44) In systemic LE (SLE), larger initial doses are required with longer periods, until response may be expected. Atra and Sato203 reported a response rate of 90% for cutaneous lesions of SLE and also described the ‘CS-sparing’ attributes of the medication. Unfortunately, systemic features of SLE do not respond as well. Thalidomide has also been successfully used in the treatment of lupus profundus (lupus panniculitis).204 Perhaps by similar mechanisms, reports detail the success of using thalidomide to treat Jessner lymphocytic infiltrate of the skin and cutaneous lymphoid hyperplasia. Graft-Versus-Host Disease. Thalidomide is considered second-line therapy for chronic GVHD (first-line therapies include systemic CS, tacrolimus, and cyclosporine) for children aged 6 months or older. Dosages range from 3 to 12 mg/kg/day for up to 2 years. In reported series, thalidomide treatment resulted in improvement in 40% to 50% of patients, often as a part of multimodality therapy. Even though less dramatic in its effects in chronic GVHD than in other conditions, thalidomide offers hope for many patients with recalcitrant or more severe forms of the disease. One case series showed a benefit in the rare but severe sclerodermatous variant of GVHD.208 Increased mortality was reported with thalidomide use in the setting of acute GVHD.209 The exact mechanism is unknown, but its immunosuppressive and anti-inflammatory actions are presumed to be central in its benefit to patients with chronic GVHD

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Prurigo Nodularis. Actinic prurigo and PN have been shown to respond to thalidomide in case reports and small series. A systematic review of studies reporting use of thalidomide (and lenalidomide) for PN showed that whereas early reports used initial thalidomide doses of 300 to 400 mg daily, many subsequent reports started at doses between 50 and 200 mg per day, titrated to effect or as needed for AE. Of the 106 patients included in the review, 72% showed significant improvement, with a decrease in pruritus by 2 to 4 weeks, and improvement in lesions by 2 months. For those achieving complete or almost complete remission, the time to remission ranged from 1 month to 8 months. Follow-up data are limited, but some patients had relapse upon discontinuation or required a second course. Peripheral neuropathy was the most common AE and developed in 37% of cases.210 Another systematic review included six studies of thalidomide use in PN. These showed good symptom response, but only two of the six studies achieved a level of evidence (LOE) 2b or higher, and many patients experienced peripheral neuropathy.211 Based on these reviews, evidence is limited but supports efficacy with fewer AE at doses of 50 to 100 mg per day. Aphthous Stomatitis. The benefit of thalidomide for refractory aphthous stomatitis has been demonstrated by several RCT. Most patients achieve remission within 4 weeks of therapy with 50 to 100 mg/day dosing, although recurrence is noted upon discontinuation. Neutrophilic Dermatoses. Thalidomide has also proved valuable in treating a number of neutrophilic dermatoses.181 A randomized placebo controlled trial for Behcet disease showed 100 mg/day to be similar in efficacy to 300 mg/day (early reports used high doses for this indication).212 Because withdrawal of the medication leads to prompt recurrence, dosing studies have been undertaken, showing lasting benefit with doses as low as 50 mg every 2 to 3 days.213 Unfortunately, ocular lesions have not been shown to respond as well to thalidomide as have mucocutaneous lesions. Less substantial evidence exists to support the use of thalidomide for the treatment of PG in doses ranging from 100 to 400 mg/day with treatment durations between 5 days to over 6 months.214 Vesiculobullous Dermatoses. There is a paucity of reports discussing the use of thalidomide for various vesiculobullous disorders.181 Citations can be found for its successful use in patients with erosive lichen planus, bullous and cicatricial pemphigoid, and recurrent erythema multiforme. Given the limited data available, it is hard to predict whether thalidomide will have significant impact on the treatment of this challenging category of disorders. Other Uses. Anecdotal evidence181 exists to support a trial of thalidomide under the following conditions: cutaneous sarcoidosis, scleromyxedema, Langerhans’ cell histiocytosis, WeberChristian disease, palmoplantar pustulosis, uremic pruritus, and postherpetic neuralgia. Contraindications. Thalidomide is absolutely contraindicated in individuals with a known sensitivity to the drug. It is also absolutely contraindicated during pregnancy. Women of childbearing potential must practice strict contraception or abstinence. Men actively engaging in sexual relations with women, who may become pregnant, must agree to the use of latex condoms. It should also not be given to individuals with existing peripheral neuropathy. The use of thalidomide is relatively contraindicated for patients with any of the following pre-existing conditions: significant hepatic or renal impairment, neuritis or other neurologic disorders, congestive heart failure, hypertension, significant constipation, other GI disorders, or hypothyroidism.

Adverse Effects Teratogenicity. Despite intense scrutiny over almost 5 decades,

the exact mechanism of thalidomide’s teratogenic potential remains unknown. Speculation has focused on the drug’s affinity for nerve tissue, as well as its ability to suppress angiogenesis, but no definitive evidence for a causal mechanism has been obtained. It is known that peak vulnerability to the drug occurs between days 21 and 36 of gestation; during this critical window, a single 100-mg dose of thalidomide results in nearly a 100% incidence of birth defects.181 The most common defect is phocomelia (deformity with underdevelopment of the arms, legs, or both), which may be accompanied by ear malformation. Abnormalities of the GI, renal, and urogenital systems have also been reported. Peripheral Neuropathy. Q40.13 The reported incidence of thalidomide-induced peripheral neuropathy varies widely. The most common presentation of the syndrome consists of mild proximal muscle weakness with symmetric painful paresthesias of the hands and feet, frequently associated with a lower limb sensory loss.215 Although motor weakness usually recovers rapidly after drug cessation, sensory dysfunction improves slowly, if at all.181 Electrophysiologic studies demonstrate a pattern consistent with axonal neuropathy, with reduction in sensory nerve action potential (SNAP) amplitude. There is relative sparing of nerve conduction velocities.215,216 Although a dose- or duration-dependent relationship between the drug and the development of neuropathy has been suggested by some, Ochonisky and colleagues217 found no such relationship in their retrospective study of 42 patients, treated for various dermatologic disorders. In fact, they found neuropathy developing in patients, with cumulative doses as low as 3 to 6 g. They reported an overall incidence of 21% to 50%, with women and the elderly experiencing the greatest risk. They concluded that individual susceptibility, possibly because of a genetic predisposition, was more important than cumulative dose of the drug, with regard to the development of neuropathy. Two more recent studies provide additional information on this important topic. Briani and coworkers noted that patients with cutaneous LE found a 50% incidence of peripheral neuropathy.218 Various factors predisposing toward the development of neuropathy have been hypothesized, but none have been proven. In addition, Bastuji-Garin and associates noted that there was a relative risk for peripheral neuropathy of 8.2, for daily doses in the range of 50 to 75 mg, and with a relative risk of 20.2 for thalidomide doses greater than 75 mg daily.219 Clearly, further careful study regarding the key factors predisposing to peripheral neuropathy risk from thalidomide is needed. Other Adverse Effects. Thromboembolic events (TE) are associated with thalidomide use at a pooled rate of 2%. In a multicenter, retrospective study of TE, in patients treated with thalidomide for CLE, the risk for thrombosis was 2.7 per 100 patient-years. The risk was highest for patients with history of arterial thrombosis, hypercholesterolemia and for active smokers, and lower for patients with a starting dose of 50 mg/day (vs. 100 mg/day) and for patients who were on hydroxychloroquine along with thalidomide. In this series, a higher risk was not demonstrated in patients with antiphospholipid antibodies or antiphospholipid syndrome. Risk was not altered by aspirin or systemic CS use.220 Endocrine effects, specifically hypothyroidism, hypoglycemia, and adrenocorticotropic hormone (ACTH) stimulation, have been rarely reported. Other, less common AE with potentially

CHAPTER 40

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TABLE 40.6 Drug Interactions—Thalidomide

Drug Category Relatively High-Risk Drug

Drug Examples

Comments

Interactionsa

Anticonvulsants

Phenytoin, carbamazepine, phenobarbital

CYP3A4 inducers; impair hormonal contraception women of childbearing potential risk teratogenicity

Rifamycins

Rifampin, rifabutin, rifapentine

same

Antifungals

Griseofulvin

same

Bisphosphonates

All members drug group

Thrombogenic with ↑ risk of thromboembolic disorders (unique risk this class jaw osteonecrosis)

Corticosteroids

Dexamethasone

same

Hormonal contraceptives

Estrogen, progesterone components

same (risk/benefit clearly in favor of using contraceptives in spite of this risk)

Vaccines—live

Zostavax, etc.

Must wait at least 3 months after therapy complete to immunize

Sedating drugs

Multiple drug classes

Excessive sedation potential in combination (ethosuximide, narcotics, alcohol, cannabinoids, sedating H1 antihistamines, anticholinergics, antidepressants, antipsychotics, benzodiazepines, etc.)

Immunosuppressants

Wide variety—immunosuppression of thalidomide relative weak

Biologics, JAK inhibitors, traditional (azathioprine, cyclosporine, mycophenolates, etc.), chemotherapy, higher dose CS with risk of severe infections and/or myelosuppression

Drugs ↑ risk peripheral neuropathy

Isoniazid, metronidazole listed

Unclear if ↑ risk of dapsone motor neuropathy

Killed, recombinant (e.g., Shigrix)

Immunize at least 2 weeks prior starting tofacitinib; if not adequate immune response, repeat in 3 months

Lower-Risk Drug Interactions Vaccines—other aOverall

highest-risk drug interactions indicated in bold italics. CS, Corticosteroid; CYP, cytochrome P-450; JAK, janus kinase. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: a Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. (http://www.hanstenandhorn.com/).

severe complications include leukopenia and exfoliative or erythrodermic reactions. A hypersensitivity reaction taking various clinical forms has been described in the HIV-positive population. An increased HIV viral load has been reported. More commonly encountered AE of less consequence include the following: drowsiness (very common), mood changes, xerostomia, brittle fingernails, nausea, constipation (common), increased appetite, peripheral edema, xerosis, pruritus, irregular menses, hyperglycemia, bradycardia, red palms, decreased libido, and dizziness.181,216 Drug Interactions. Table 40.6 lists drug interactions for thalidomide. Thalidomide has additive effects with other sedative agents, such as (but not limited to) alcohol, barbiturates, chlorpromazine, or reserpine, with resultant increased CNS depression. It has been shown to antagonize the effects of histamine, serotonin, acetylcholine, and the prostaglandins in vitro.185 To date, there are no reports documenting thalidomide’s concomitant use with various CYP inducers or inhibitors. Extreme caution must be used when patients receiving thalidomide are also taking medications with the potential to interfere with hormonal contraceptives. Monitoring Guidelines Thalomid REMS Program for Monitoring Thalidomide Therapy. Since mid-1999, thalidomide has been approved for

marketing, under a special restricted distribution program developed by the manufacturer (Celgene) and the FDA (see Box 40.7).

Only physicians and pharmacists registered with the THALOMID REMS program are permitted to prescribe and dispense the product. Registration may be initiated by visiting CelgeneRiskManagement.com or by contacting the Celgene Corporation at 1-888-423-5436. After mutual agreement has been reached between the physician and the patient, regarding the medical necessity for thalidomide, informed consent must be formally registered. Standardized informed consent forms and important product information are provided, upon registering with the THALOMID REMS program. A sample consent form and package insert can also be obtained by contacting the Celgene Corporation. Neurologic Monitoring. Q40.13 Before the first dose, a complete history and physical examination should be performed, with emphasis on detecting pre-existing neurologic defects. Obtaining at least one and preferably two SNAP amplitudes, as a baseline should be considered if indicated by significant historical or physical findings, suggesting possible peripheral neuropathy.217 After therapy is initiated, clinical evaluation with emphasis on neurologic findings, such as numbness, tingling, or pain in the hands and feet, should be carried out at least monthly for the first 3 months, and then every 3 to 6 months thereafter, as indicated. SNAP measurements should at least be considered when clinically warranted, and after every 6 months of therapy, whichever is sooner, to detect asymptomatic neuropathy.

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• BOX 40.7 Thalidomide Monitoring Guidelines Baseline • Determine the patient’s ability to comprehend the drug risks and willingness to sign the consent form, as well as willingness to participate in ongoing monitoring programs

Laboratory Testing • Pregnancy test: serum (or urine test of adequate sensitivity) in women of childbearing potential • Complete blood count (CBC) with platelets • Liver function panel

Neurologic Evaluation • Clinical neurologic examinationa • At least one, preferably two, measurements of sensory nerve action potential (SNAP) amplitudesb if indicated by history of peripheral nervous disease or positive history or physical findings

Follow-Up Laboratory Testing • Pregnancy tests: weekly for first 4 weeks, then monthly for women of childbearing potential with regular menses, or every 2 weeks for irregular menses and as clinically indicated • Monthly CBC with platelet determination, until dose is stable, then every 2–3 months. • Liver function panel every 2-3 months.

Neurologic Evaluation • Clinical evaluation to include neurologic examination, at least monthly for the first 3 months, thereafter every 1–6 months, as indicated • Consider SNAP measurements after every 6 months, or when clinically indicated aClinical

neurologic examination should include a subjective review of sensory and motor function, as well as an objective search for distal hypesthesia or paresthesia, muscle weakness, or ankle jerk reflex depression. bSNAP amplitudes should be measured from at least three nerves. Two measurements allow a confidence interval to be calculated for an individual patient. A fall of 40% or more from baseline should be considered significant. A fall of 30% to 40% from baseline indicates the need for more frequent neurologic examination and SNAP measurement, as well as requiring re-evaluation of the necessity for continued thalidomide therapy. More frequent surveillance is needed if laboratory values are abnormal or with high-risk patients.

Pregnancy Prevention. In women, effective birth control must be in place for at least 1 month before starting thalidomide, while taking thalidomide, during any treatment breaks, and for 1 month after completing therapy. A negative pregnancy test (minimum sensitivity of 50 mIU/mL) should be obtained within 24 hours of beginning therapy. Fertile men should be advised to wear a latex condom during sexual intercourse, because thalidomide has been detected in semen.217,218 Pregnancy Monitoring. A negative pregnancy test with a sensitivity of at least 50 mIU/mL must be obtained within 24 hours before initiating thalidomide. Pregnancy tests are then required weekly for the first 4 weeks, then monthly, for women with regular menses. Pregnancy tests should be performed every 2 weeks for women with irregular menses.217,221 These very careful monitoring guidelines to exclude pregnancy are clearly documented in the THALOMID REMS program information. Far simpler than the aforementioned monitoring would be to completely avoid thalidomide use in women of childbearing potential. Other Laboratory Testing. In addition, a baseline CBC with platelets should be obtained and monitored, initially monthly and moving rapidly to every 3 to 6 months. Testing of hepatic transaminases at similar intervals is a reasonable approach as well.

Vitamin E Vitamin E (tocopherol) is a fat-soluble vitamin whose exact biochemical mechanisms are unclear. Many of this vitamin’s actions have been attributed to its antioxidant properties. Natural sources of vitamin E include vegetable oils, leafy vegetables, milk, eggs, meat, and some nuts. Although clinical deficiency of vitamin E is exceedingly rare, supplements are readily available and commonly used. In the industrialized world, no cutaneous signs or symptoms have been reported from vitamin E deficiency.222 Dermatologic conditions for which there is evidence of vitamin E efficacy include epidermolysis bullosa, CCLE, yellow nail syndrome, granuloma annulare, and claudication contributing to skin ulceration.223 There is ongoing debate over the possible role of vitamin E in skin cancer prevention. Its utility in reducing AE associated with oral retinoid therapy has been anecdotally reported.224 Although anecdotal reports of success exist, there are no clinical studies to support the vitamin’s use for the treatment of psoriasis, atopic dermatitis, dermatitis herpetiformis, porphyria, or subcorneal pustular dermatosis. Suggested dosages for the therapeutic use of vitamin E vary widely. Its ingestion may enhance the effects of oral anticoagulants. In addition, in light of recent work concluding that highdosage supplementation (at least 400 IU daily) may nonspecifically increase mortality levels, it would seem wise to limit its use to well-informed patients with a definitive chance of benefit.225

Zinc Sulfate Zinc is a trace element involved in many cellular processes. Deficiency has been reported secondary to dietary inadequacy, especially among those dependent on total parenteral nutrition and in breastfed infants.226 Classic cutaneous findings associated with zinc deficiency are circumorificial and acral dermatitis and accompanying diarrhea. Zinc deficiency is mimicked by acrodermatitis enteropathica, an autosomal-recessive disorder of zinc metabolism that presents in infancy. True dietary deficiencies and acrodermatitis enteropathica can be readily detected by obtaining serum zinc levels. Both usually respond rapidly to zinc supplementation. Common doses of zinc replacement are in the range of 1 to 2 mg/ kg daily of elemental zinc in 3 divided doses. Zinc has been used with inconsistent success in the treatment of various acneiform conditions, alopecia, and verrucae. Recent publications suggest that zinc sulfate may be useful in treating acute cutaneous leishmaniasis and perhaps leg ulcers in persons with low zinc levels.227,228

Gabapentin and Pregabalin Gabapentin (1-[aminomethyl]cyclohexaneacetic acid) and pregabalin ([3S]-3-[aminomethyl]-5-methylhexanoic acid) were developed as antiepileptic medications, but are now used to treat neuropathic pain. They are both analogs of γ-aminobutyric acid (GABA). However, they do not interact with GABA receptors. Their exact mechanism of action is unclear, but it is thought that they inhibit the α2δ subunit of voltage-dependent calcium channels in the dorsal root ganglion and the spinal cord horn, reducing calcium influx and subsequent release of excitatory neurotransmitters, increasing the threshold for neuronal excitation. Gabapentin is absorbed slowly after oral administration, with maximum plasma concentrations attained within 34 hours. Orally administered gabapentin exhibits a saturable absorption in a nonlinear process, such that plasma concentrations of gabapentin do not increase proportionally

CHAPTER 40

• BOX 40.8 Drug Risks Profile—Gabapentin Contraindications Hypersensitivity to gabapentin or components of formulation

Boxed Warnings None listed

Warnings & Precautionsa Psychiatric

Neurologic

Suicidal behavior and ideation (higher risk in use for seizures)

Sudden unexplained deaths (seizure patients—see text) aDizziness, sedation, somnolence, other sx of CNS depression

Renal aSignificant

caution with impaired renal function

Hypersensitivity Reactions aDrug

hypersensitivity syndrome (DRESS)

Pregnancy Prescribing Status Traditional US Food and Drug Administration rating—category C

Newer ratingb—Moderate-High Risk

aUnder “Warnings

& Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid. bSee Chapter 65, Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings. CNS, Central nervous system; DRESS, drug reaction with eosinophilia and systemic symptoms. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https:// www.wolterskluwercdi.com/facts-comparisons-online/).

with increasing dose. In contrast, orally administered pregabalin is absorbed more rapidly, with maximum plasma concentrations attained within 1 hour. Absorption of pregabalin is linear, with plasma concentrations increasing proportionately with increasing dose. The absolute bioavailability of gabapentin drops from 60% to 33%, as the dosage increases from 900 to 3600 mg/day, whereas the absolute bioavailability of pregabalin remains at 90% or higher irrespective of the dosage.229 These drugs do not bind plasma proteins, and are not metabolized by hepatic enzymes. Gabapentin and pregabalin are excreted renally with elimination half-lives of about 6 hours. Doses of both gabapentin and pregabalin should be adjusted for renal impairment, based on creatinine clearance; no dosage adjustments are required for hepatic impairment. Box 40.8 presents the drug risks profile for gabapentin. US Food and Drug Administration-Approved Indications.

Approved indications for gabapentin include partial seizures and postherpetic neuralgia (PHN). Pregabalin is FDA approved for fibromyalgia, neuropathic pain associated with spinal cord injury or diabetes, PHN, and partial seizures. Postherpetic Neuralgia. PHN is defined as the persistence of pain lasting 12 weeks after onset of herpes zoster. A meta-analysis of RCT, examining the use of gabapentin for PHN, demonstrated reduction in pain intensity and improved sleep quality. AE that were significantly increased in patients receiving gabapentin were somnolence, dizziness, and peripheral edema.230 Similarly, a meta-analysis of placebo-controlled studies of pregabalin for PHN showed a decrease in pain scores and reduced sleep interruption.231 Recommended gabapentin dosing for PHN is 300 mg once on day 1, 300 mg twice daily on day 2, and 300 mg 3 times daily on day 3, then increase as needed, up to 1.8 to 3.6 g/day in divided doses. For extended release formulation, dosing is 300 mg once daily; increase by 300 mg each day, up to 900 mg once

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daily. Further increase as needed, up to 1.8 g once daily. Pregabalin dosing is 150 mg/day in divided doses (75 mg twice daily or 50 mg, 3 times daily); may increase to 300 mg/day within 1 week based on response and tolerability; after 2 to 4 weeks, may further increase up to the maximum dose of 600 mg/day. For extended release formulations, start 165 mg once daily; may increase to 330 mg once daily within 1 week, based on response and tolerability; after 2 to 4 weeks, may further increase up to the maximum dose of 660 mg/day. Off-Label Uses Chronic Pruritus. Uremic pruritus is a common problem

among dialysis-dependent patients. Gabapentin has been shown to be effective for itch, not responsive to antihistamines and moisturizers in two RCT given at a dose of 300 to 400 mg/hemodialysis session.232,233 Lower doses have also been reported as effective (e.g., 100 mg/hemodialysis session).234,235 Pregabalin has also been studied in RCT for uremic pruritus and was effective at a dose of 75 mg/day, given twice weekly.236 Other forms of chronic itch treated with gabapentin include brachioradial pruritus, nostalgia paresthetica, scalp dysesthesia, PN. Doses used for these conditions in case reports, and case series ranged broadly from 200 to 1800 mg/day.237 Pregabalin has been reported as a therapy for polycythemia vera–related pruritus, PN and scalp dysesthesia at doses ranging from 75 to 300 mg/day. Adverse Effects. The most common AE of gabapentin and pregabalin is drowsiness/sedation, followed by dizziness, ataxia, and fatigue. Peripheral edema occurs in up to 8% of exposures. Pregabalin has a similar AE profile with risk for the following in greater than 10% of exposure: peripheral edema, dizziness, drowsiness, headache, fatigue, weight gain, xerostomia, visual field loss and blurred vision. Other than creatinine at baseline, no laboratory monitoring is required for patients on gabapentin or pregabalin. Patients should be monitored for depression, behavior changes, and suicidality. Gabapentin and pregabalin should be disconcontinued gradually over 1-2 weeks following chronic use to minimize increased seizure risk (in patients with epilepsy) and other withdrawal symptoms (confusion, diaphoresis, tachycardia, and irritability). Prescribers should also be aware of possible misuse of gabapentin and pregabalin. Pregabalin was placed into Schedule 5 of the Controlled Substances Act by the Drug Enforcement Administration in 2005. Gabapentin has been reclassified as a Schedule 5 controlled substance in several states. This follows a trend of increased use in combination with opioids, in users seeking a stronger high. The combination potentially makes opioids more lethal.

Acknowledgment The authors would like to acknowledge Drs. Keith G. LeBlanc Jr. and Alfred L. Knable Jr. for the contributions to the previous edition of this chapter.

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223. Keller KL, Fenske NA. Uses of vitamins A, C, and E and related compounds in dermatology: a review. J Am Acad Dermatol. 1998;39(4 Pt 1):611–625. 224. Salasche SJ, Lebwohl M. Clinical pearl: vitamin E (alphatocopherol) 800 IU daily, may reduce retinoid toxicity. J Am Acad Dermatol. 1999;41(2 Pt 1):260. 225. Miller 3rd ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1):37–46. Zinc Sulfate 226. Bilinski DL, Ehrenkranz RA, Cooley-Jacobs J, McGuire J. Symptomatic zinc deficiency in a breast-fed, premature infant. Arch Dermatol. 1987;123(9):1221–1224. 227. Sharquie KE, Najim RA, Farjou IB, Al-Timimi DJ. Oral zinc sulfate in the treatment of acute cutaneous leishmaniasis. Clin Exp Dermatol. 2001;26(1):21–26. 228. Wilkinson EA, Hawke CI. Oral zinc for arterial and venous leg ulcers. Cochrane Database Syst Rev. 2000;(2):CD001273. Gabapentin and Pregabalin 229. Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49(10):661–669. 230. Zhang M, Gao CX, Ma KT, et al. A meta-analysis of therapeutic efficacy and safety of gabapentin in the treatment of postherpetic neuralgia from randomized controlled trials. Biomed Res Int. 2018;2018:7474207. 231. Wang SL, Wang H, Nie HY, Bu G, Shen XD, Wang H. The efficacy of pregabalin for acute pain control in herpetic neuralgia patients: a meta-analysis. Medicine (Baltimore). 2017;96(51):e9167. 232. Gunal AI, Ozalp G, Yoldas TK, Gunal SY, Kirciman E, Celiker H. Gabapentin therapy for pruritus in hemodialysis patients: a randomized, placebo-controlled, double-blind trial. Nephrol Dial Transplant. 2004;19(12):3137–3139. 233. Naini AE, Harandi AA, Khanbabapour S, Shahidi S, Seirafiyan S, Mohseni M. Gabapentin: a promising drug for the treatment of uremic pruritus. Saudi J Kidney Dis Transpl. 2007;18(3):378–381. 234. Manenti L, Vaglio A, Costantino E, et  al. Gabapentin in the treatment of uremic itch: an index case and a pilot evaluation. J Nephrol. 2005;18(1):86–91. 235. Razeghi E, Eskandari D, Ganji MR, Meysamie AP, Togha M, Khashayar P. Gabapentin and uremic pruritus in hemodialysis patients. Ren Fail. 2009;31(2):85–90. 236. Yue J, Jiao S, Xiao Y, Ren W, Zhao T, Meng J. Comparison of pregabalin with ondansetron in treatment of uremic pruritus in dialysis patients: a prospective, randomized, double-blind study. Int Urol Nephrol. 2015;47(1):161–167. 237. Matsuda KM, Sharma D, Schonfeld AR, Kwatra SG. Gabapentin and pregabalin for the treatment of chronic pruritis. J Am Acad Dermatol. 2016;75(3):619–625.e6.

PART VIII

Topical Drugs for Infectious Diseases

41 Topical Antibacterial Agents COLTON NIELSON, SYLVIA HSU AND KIRAN MOTAPARTHI

QUESTIONS Q41.1 How effective is bacitracin versus mupirocin in eliminating nasal staphylococcal carriage? (Pgs. 466, 470)

Q41.8 What characteristic complication has been reported following the use of topical gentamicin in neonates? (Pg. 471)

Q41.2 Concerning postoperative topical antibacterial use, (1) what are the pros and cons of routinely applying petrolatum versus a topical antibacterial agent for ‘clean’ dermatologic surgical wounds, and (2) how common is contact sensitization with bacitracin, neomycin, and mupirocin? (Pgs. 466, 468, 469, 470x2, 471)

Q41.9 What is the antimicrobial spectrum of activity of iodoquinol? (Pg. 472)

Q41.3 How common is anaphylaxis with topical bacitracin use and what factors increase the incidence of this complication? (Pg. 468) Q41.4 Do bacitracin and neomycin ‘cross-react’ or ‘co-react’ with regard to simultaneous contact sensitization? (Pgs. 468, 469) Q41.5 Regarding methicillin-resistant Staphylococcus aureus (MRSA) resistance to mupirocin, (1) how common is this resistance, and (2) what are the underlying mechanisms involved in mupirocin resistance? (Pg. 470) Q41.6 What is the role of mupirocin in the management of atopic dermatitis? (Pg. 470) Q41.7 What are the mechanisms of action underlying the microbiologic activity of retapamulin, and how do these mechanisms explain why cross-resistance between retapamulin and other topical antibacterials is uncommon? (Pg. 471x2)

Q41.10 What are the mechanisms by which benzoyl peroxide benefits acne vulgaris patients? (Pg. 472) Q41.11 Which topical antibacterial may degrade tretinoin when used in combination? (Pg. 474) Q41.12 How common is Propionibacterium acnes resistance to benzoyl peroxide, clindamycin, and erythromycin applied topically? (Pgs. 474, 475) Q41.13 How is erythromycin resistance in P. acnes overcome? (Pg. 475) Q41.14 Concerning metronidazole, (1) what are the mechanisms by which metronidazole benefits patients with rosacea, and (2) how active is metronidazole against Demodex mites? (Pg. 476x2) Q41.15 Which topical antibacterial agent may have utility in the treatment of seborrheic dermatitis? (Pg. 477) Q41.16 What is the risk of significant hemolysis in patients treated with topical dapsone? (Pg. 478) Q41.17 Which topical antiseptic has been associated with ototoxicity? (Pg. 479)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R ACD Allergic contact dermatitits AE Adverse effect(s) FDA Food and Drug Administration G6PD Glucose-6-phosphate dehydrogenase HIV Human immunodeficiency virus MRSA Methicillin-resistant Staphylococcus aureus

Introduction The major advantage in the topical use of an antibacterial agent (Fig. 41.1) is the ability to achieve high local drug concentrations with minimal systemic absorption, thus minimizing the risk of systemic adverse effects (AE). This chapter summarizes the current scientific information on commonly used topical antibacterial

MRSE Methicillin-resistant Staphylococcus epidermidis NACDG North American Contact Dermatitis Group PPARγ Peroxisome proliferators-activated receptor γ SPF Sun protection factor TNF Tumor necrosis factor

agents and their role in skin diseases. In addition, the potential of allergic contact sensitivity from several of the topical antibacterial agents is discussed. The chapter is divided into two broad categories of topical antibacterial agents: (1) drugs used primarily for wound care and minor topical bacterial infections, and (2) drugs used primarily for acne and rosacea. Popular topical antiseptic agents are briefly discussed at the end of the chapter.

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S

N C

CH

CHCH2CH3

NH 2

CH3

O

L Leu L Asn

D Glu

L IIe D Orn L αLys

L IIe

L His D Asp D Phe

Bacitracin

O

O

O

(CH2)8 O

OH

OH O OH

OH Mupirocin

H

Cl

N N O

O

HO OH

S

OH Clindamycin

• Fig. 41.1

Topical Antibacterial Agents (Bacitracin, Mupirocin, Clindamycin).

Drugs Used for Wound Care and Minor Topical Bacterial Infections Bacitracin Pharmacology

Bacitracin is a polypeptide antibacterial agent produced by the Tracey I strain of Bacillus subtilis.1 Bacitracin complexes with the carrier protein C55-prenol pyrophosphatase, which is involved in bacterial cell wall synthesis (Table 41.1).2 When complexed with zinc (about 7%), bacitracin becomes less water soluble, but the shelf-life of the drug increases from 2 to 5 years.3 Bacitracin can be combined with polymyxin B, and possibly also neomycin, to provide a wider spectrum of bacterial coverage (Table 41.2). Bacitracin is classified as pregnancy category C (Table 41.3). Microbiologic Activity (see Table 41.1). Bacitracin is active against Staphylococcus aureus, Streptococcus pneumoniae, Neisseria spp, Haemophilus influenzae, Treponema pallidum, Actinomyces, and Fusobacterium spp. It has minimal Gram-negative coverage

and is not active against Pseudomonas, Nocardia, Enterobacteriaceae, Candida, or Cryptococcus.4 Clinical Use Dermatologic Uses. Bacitracin, in combination with cetrim-

ide (an antiseptic) and polymyxin B and possibly neomycin, significantly reduces S. aureus contamination in artificially inoculated normal skin and wounds.5,6 Q41.1 However, bacitracin is only 44% effective for eliminating nasal carriage of S. aureus, compared with 94% reduction with mupirocin.7,8 In a randomized trial comparing topical mupirocin, topical bacitracin, and oral cephalexin for the treatment of impetigo, bacitracin was significantly inferior and associated with frequent treatment failure.9 Q41.2 A double-blind study comparing bacitracin with white petrolatum found no statistical difference in the postoperative infection rate in dermatologic surgery patients. In this study, 90% of the wound infections in the petrolatum group were because of methicillin-sensitive S. aureus (MRSA), whereas the patients treated with bacitracin grew ciprofloxacin-sensitive

TABLE Spectrum of Coverage and Mechanisms of Action of Topical Antibacterial Agents Used for Minor Topical 41.1 Antibacterial Infections and Wound Care

Name

Bacterial Coverage

Mechanism of Action

Origin

Bacitracin

Bactericidal against Gram (+) and Neisseria species

Interferes with bacterial wall synthesis; occurs by inhibition of phospholipid receptors involved in peptidoglycan synthesis

Licheniformis group of Bacillus subtilis

Polymyxin B

Bactericidal against Gram (–) bacteria only; effective against Pseudomonas aeruginosa

Increases permeability of bacteria cell membrane; occurs by interacting with phospholipid components of membrane

Bacillus polymyxa Bacillus subtilis

Neomycin

Bactericidal against Gram (+) and Gram (–) bacteria; good Staphylococcus aureus coverage

Inhibits protein synthesis; occurs by binding to 30s subunit of ribosomal RNA; end result is misreading of bacterial genetic code

Aminoglycoside antibiotic derived from Streptomyces fradiae

Mupirocin

Bactericidal against methicillinresistant S. aureus; Streptococcus pyogenes

Inhibits bacterial RNA and protein synthesis; occurs by reversibly binding to bacterial isoleucyl transfer RNA synthetase

Pseudomonas fluorescens

Retapamulin

Bacteriostatic against S. pyogenes, mupirocin-resistant and methicillinresistant S. aureus, anaerobes

Inhibits bacterial protein synthesis; occurs by binding to protein L3 on 50s ribosomal subunit

Pleuromutilin antibiotic derived from Clitopilus scyphoides

Ozenoxacin

Bacteriostatic against Propionibacterium acnes, S. aureus, S. pyogenes, including fluoroquinolone resistant organisms

Inhibits bacterial DNA synthesis via inhibition of DNA gyrase A and topoisomerase IV

Nonfluorinated quinolone

Gentamicin

Bactericidal against Gram (+) and Gram (–) organisms; coverage includes P. aeruginosa

Inhibits bacterial protein synthesis; occurs by irreversibly binding to 30s ribosomal subunits

Aminoglycoside antibiotic derived from Micromonospora purpurea

Silver sulfadiazine

Bactericidal against Gram (+) and Gram (–) organisms

Binds to bacterial DNA and inhibits its replication

Synthesized from reaction of silver nitrate and sodium sulfadiazine

Iodoquinol

Active against Gram (+) and Gram (–) organisms

Unknown

Synthetic halogenated derivative of quinolone

DNA, Deoxyribonucleic acid; RNA, ribonucleic acid.

TABLE Topical Antibacterial Agents Used for Wound Care and Minor Topical Antibacterial Infections—Drugs 41.2 Discussed in This Chapter

Generic Name

Trade Name

Manufacturer

Generic Available

Bacitracin

Bacitracin

Various

Yes

15 g, 30 g, 120 g, 454 g

Polymyxin (B)

Polysporin,a

others

Warner Wellcome, others

Yes

15 g, 30 g

Neomycin

Neosporin,b others

Warner Wellcome, others

Yes

15 g

15 g, 30 g

Mupirocin

Bactroban

SmithKline Beecham Ortho Dermatologics

Yes

22 g

22 g, 15 g, 30 g

Centany

Cream Tube Sizes

Retapamulin

Altabax, Altargo

GlaxoSmithKline

No

Ozenoxacin

Xepi Ozanex

Medimetriks Cipher

No

10 g, 30 g, 45 g

Gentamicin

Garamycin

Schering

Yes

15 g, 30 g

Silver sulfadiazine

Silvadene, others

Hoechst

Yes

20–1000 g

Iodoquinol

Vytone, Alcortin A, Dermazene, others

Primus, Novum Pharma

Yes

30 g, 45 g

aPolysporin bNeosporin

Ointment Tube Sizes

Special Formulations

Powder—10 g

5 g, 15 g

15 g, 30 g

and generic ‘double antibiotics’ contain bacitracin and polymyxin B—polymyxin B is not available as individual product. and generic ‘triple antibiotics’ contain bacitracin, polymyxin B, and neomycin—neomycin is also not available as individual product.

Gel—2 g

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TABLE Pregnancy Categories of Agents Used for 41.3 Wound Care and Minor Topical Antibacterial

TABLE Patch Testing for Contact Dermatitis From 41.4 Topical Antibacterial Agents

Infections Name

Pregnancy Categorya

Name

Patch Testing Ingredients

Contact Sensitizationa

Bacitracin

C

Bacitracin

20% in petrolatum

0.9%

Polymyxin B

B

Polymyxin

3% in petrolatum

Rare

Neomycin

D

Neomycin

20% in petrolatum

0.09%–1.1%

Mupirocin

B

Mupirocin

2% in petrolatum

Rare

Retapamulin

B

Gentamicin

20% in petrolatum

Rare

Ozenoxacin

Unknown

Silver sulfadiazine

5% in petrolatum

Rare

Gentamicin

C

Benzoyl peroxide

0.2%–1%

Silver sulfadiazine

B

5% gel, 2% in petrolatum

Clindamycin

1% aqueous solution

Rare

Iodoquinol

C Erythromycin

1%–5% in petrolatum

Rare

Metronidazole

1% in petrolatum

Rare

Azelaic acid

20% in cream

Rare

aEditor’s

note (SEW) - refer to Chapter 65 for updated ratings on selected drugs in this and subsequent Pregnancy Category tables.

Gram-negative bacteria. Given the higher cost of treating Gramnegative infections, the 0.9% rate of contact dermatitis, and the higher cost of bacitracin, it is less expensive to treat clean dermatologic surgical wounds with white petrolatum.10 Adverse Effects. There have been no published reports on the topical absorption of bacitracin into skin. However, no significant systemic absorption of bacitracin occurs after bladder irrigation.11 Common AE include localized itching and burning. Q41.2 The North American Contact Dermatitis Group (NACDG) found that 9.2% of patients with allergic contact dermatitis (ACD) had a positive patch test to bacitracin.12 Bacitracin is a frequent allergen in patients with chronic stasis dermatitis or keratoconjunctivitis.13 Over 12% of patients with stasis dermatitis and 24% of patients with chronic leg ulcers have positive patch tests to bacitracin.14,15 Barrier disruption and chronicity of use in these clinical settings may allow the development of contact dermatitis.16,17 Thus, long-term use on nonintact skin, encountered in stasis ulcers or chronic inflammatory dermatoses, may lead to an increased risk of contact allergy. In dermatologic surgery, postoperative use of bacitracin is associated with an 8% overall incidence of ACD.18 Patch testing is performed with 20% bacitracin in petrolatum (Table 41.4). Given that zinc bacitracin is less soluble than bacitracin, it may provide false-negative test results. In addition, a 48-hour patch test reading may miss a positive reaction, which may not be manifest until 96 hours.3 Q41.3 To date, there has been a significant number of reported cases of anaphylactic shock because of topical bacitracin.13,19–24 Most cases involved patients who had used bacitracin on nonintact skin such as ulcers. Q41.4 Bacitracin often co-reacts—but does not cross-react—with neomycin, such that patch testing to both may uncover a neomycin allergy. It is believed that the co-reacts is attributed to coincidental sensitization, as bacitracin is chemically unrelated to neomycin, but both antibacterial agents are commonly found in combination25 (Table 41.5).

aRate

in all patients.

Table 41.1). The antibacterial agent destroys bacterial membranes with a surface detergent-like mechanism.26 Polymyxin B may be administered intravenously or intramuscularly. However, it is commonly added to topical formulations with bacitracin, and possibly neomycin as well, to broaden coverage against Gramnegative bacteria, especially Pseudomonas aeruginosa. Polymyxin B is classified as pregnancy category B (see Table 41.3). Microbiologic Activity (see Table 41.1). Polymyxin B is bactericidal in  vitro against Gram-negative bacteria including Proteus mirabilis, P. aeruginosa, and Serratia marcescens. In  vitro activity has also been demonstrated against Acinetobacter baumannii, a multidrug-resistant Gram-negative organism associated with wound infections leading to septicemia.27 This antibacterial agent is not effective against Gram-positive bacteria or fungi.26 Clinical Use Dermatologic Uses. Polymyxin B is usually combined with

other topical antibacterial agents to broaden its bacterial coverage. For example, the ‘triple antibiotic’ combination of neomycin, bacitracin, and polymyxin B is a popular, inexpensive, over-thecounter formulation for the treatment of minor skin wounds. Adverse Effects. Contact allergy to polymyxin B in the absence of concomitant positive reactions to neomycin, bacitracin, or oxytetracyclines is very rare.28 Additionally, polymyxin B is not a significant allergen in postoperative wounds in dermatologic surgery patients.18 Because polymyxin B binds avidly to cell membranes, there is little systemic absorption and few systemic reactions even when applied to open wounds,2 although one case of reversible acute renal failure was reported.29 When contact allergy is suspected, patch testing may be done with 3% polymyxin B in petrolatum (see Table 41.4).

Polymyxin B

Neomycin

Pharmacology

Pharmacology

Polymyxin B is a cationic, branched, cyclic decapeptide, isolated from the aerobic Gram-positive rod, Bacillus polymyxa (see

Neomycin is a bactericidal aminoglycoside antibacterial agent produced by Streptomyces fradiae.30 It binds to the 30s subunit of the

CHAPTER 41

Topical Antibacterial Agents

469

TABLE Key Concepts—Topical Antibacterial Agents Used for Wound Care and Minor Topical Antibacterial Infections 41.5

Name

Comments

Bacitracin

Relatively common sensitizer, especially with stasis dermatitis Common co-reactions with neomycin (not a true cross-reaction) Anaphylaxis possible with application to an ulcer bed

Polymyxin B

Available in combination with bacitracin as Polysporin; combination is often called a ‘double antibiotic’ Good Gram (–) bacterial coverage, including Pseudomonas organisms

Neomycin

Also a relatively common sensitizer, especially with stasis dermatitis In combination with bacitracin and polymyxin B is known as Neosporin or a ‘triple antibiotic’ Good Gram (+) bacterial coverage—notably Staphylococcus aureus

Mupirocin

Very uncommon sensitizer Is very effective in eradicating nasal S. aureus carriage state Resistant strains of S. aureus are possible

Retapamulin

Low potential for cross-resistance with other commonly used topical antibacterials because of unique target of action Good Gram (+) bacterial coverage, including mupirocin-resistant S. aureus

Ozenoxacin

Good Gram (+) bacterial coverage, including Propionibacterium acnes, S. aureus, Streptococcus pyogenes, including levofloxacin resistant organisms Few reported adverse reactions

Gentamicin

Uncommon sensitizer Good Gram (–) bacterial coverage, notably Pseudomonas organisms

Silver sulfadiazine

Very active against Pseudomonas aeruginosa in burns Can cross-react with patients who have a sulfonamide allergy

Iodoquinol

May be useful in treating fungal infections complicated secondarily by bacteria Broad spectrum coverage against bacteria, dermatophytes, and yeasts

bacterial ribosome to inhibit protein synthesis. It may also inhibit bacterial deoxyribonucleic acid (DNA) polymerase (see Table 41.1).31 Neomycin is classified as pregnancy category D (see Table 41.3). Microbiologic Activity (see Table 41.1). Neomycin has good coverage against most clinically important Gram-negative and some Gram-positive organisms, including Escherichia coli, H. influenzae, Klebsiella spp, Proteus spp, S. aureus, and Serratia spp. It does not cover P. aeruginosa or anaerobic bacteria such as Bacteroides spp. Moreover, neomycin has only weak activity against streptococci.26,32 Because resistance to neomycin has been reported in both Gram-positive and Gram-negative bacteria, neomycin is virtually always used in combination with other topical antibacterial agents. Bacitracin is typically added for its Gram-positive coverage, whereas polymyxin B is added to provide coverage of Pseudomonas spp. Clinical Use Dermatologic Uses. Neomycin is useful for treating minor

wounds and cutaneous infections. It is used in combination with bacitracin to achieve optimal staphylococcal and streptococcal coverage. Adverse Effects. As with other aminoglycosides, systemic toxicity to neomycin includes ototoxicity and nephrotoxicity. Systemic absorption and toxicity do not occur when the antibacterial agent is used topically on minor skin lesions. Neomycin-related deafness has been reported, usually involving a neomycin solution to irrigate a large wound.33 There have been rare reported cases of deafness from using ear drops containing neomycin. Ear drops containing an ototoxic agent should not be used in patients with tympanic membrane perforation.34 To reduce the potential for

sensitization, resistance, or toxicity, it is recommended that no more than 1 g per day of a topical preparation containing neomycin be used, for a maximum of 7 days.32 Q41.2 The overall prevalence of allergic contact sensitivity to neomycin in the United States has been reported to range from 0.09% to 1.1%,35,36 but 10% of patients with ACD have positive patch testing to neomycin.12 In dermatologic surgery, neomycin is the most common cause of postoperative ACD and should be avoided.18 Regarding chronic use, studies indicate that in patients suffering from leg ulcers, between 9% and 13% of patients patchtested positive to neomycin.15,37 Patch testing is done by applying 20% neomycin sulfate in petrolatum under occlusion for 48 hours (see Table 41.4). Although the majority of tests are positive in 96 hours, it may take 7 days to become positive.32 Neomycin potentially cross-reacts with streptomycin, kanamycin, gentamicin, paromomycin, spectinomycin, and tobramycin.38 Q41.4 As previously mentioned, neomycin often co-reacts, but does not crossreact, with bacitracin. Therefore, patch testing to both may uncover a bacitracin allergy, and this co-reaction represents coincidental sensitization.25

Mupirocin Pharmacology

Mupirocin, formerly pseudomonic acid, is a major metabolite of Pseudomonas fluorescens. It inhibits bacterial isoleucyl-transfer ribonucleic acid (tRNA) synthetase, thereby hindering bacterial RNA, protein, and cell wall synthesis (see Table 41.1).39 The drug is bactericidal at concentrations achieved by topical administration.26 Topical absorption is minimal,40 and cutaneous

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metabolism is less than 3%, leaving most of the drug on the skin for antibacterial activity.26 Mupirocin may be less effective on weeping wounds because 95% of the drug is protein bound.41 Mupirocin is available as a 2% ointment in polyethylene glycol (Bactroban ointment and Centany ointment),42 or in white soft paraffin/Softisan 649 (Bactroban Nasal), and as a 2% cream in mineral oil (Bactroban cream). Mupirocin is classified as pregnancy category B (see Table 41.3). Microbiologic Activity (see Table 41.1). Mupirocin has excellent activity against S. aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and β-hemolytic streptococci. In addition, it covers MRSA.42 Mupirocin is not active against anaerobic bacteria, P. aeruginosa, Enterococcus faecalis, Enterococcus faecium, Streptococcus bovis, fungi, or normal skin flora such as Corynebacterium, Micrococcus, and Propionibacterium spp.26,42 Q41.5 Mupirocin resistance, encountered almost exclusively in strains of MRSA and methicillin-resistant Staphylococcus epidermidis (MRSE), has increased recently, and prior exposure to mupirocin is a strong predictor for resistance.43,44 Low-level resistance results from mutations in the native ileS gene encoding isoleucyl t-RNA synthetase, whereas high-level resistance is mediated by transfer of the plasmid-encoded ileS-2 gene, which results in expression of another isoleucyl t-RNA synthetase.45–47 Resistance to mupirocin does not negatively affect the ability of these bacteria to survive or reproduce,48,49 and it is estimated that 3.1% of MRSA strains demonstrate high-level resistance.43 Clinical Use Cutaneous Bacterial Infections. Mupirocin is used to treat

skin infections frequently initiated by staphylococci and streptococci, including impetigo, folliculitis, impetiginized eczema, burns, lacerations, and leg ulcers. In a Cochrane systematic review of 57 trials, topical mupirocin was more effective than oral erythromycin for impetigo.50 Mupirocin ointment is effective for almost all patients with staphylococcal folliculitis and results in cure for 75% of patients.51,52 Staphylococcal Colonization. Q41.1 Intranasal mupirocin is effective for the elimination of staphylococci, even MRSA, from chronic carriers.8,53,54 Most recent studies advocate twice-daily application for 5 days. Prolonged suppression of nasal staphylococcal carriage is achieved by weekly dosing or monthly courses.55 In healthy adults, intranasal mupirocin is effective in decolonizing nasal, but not extranasal, sites.56 To eliminate carriage of MRSA in immunocompetent patients with recurrent pyoderma caused by S. aureus, the best regimen is mupirocin ointment applied to the nares two to three times per day in combination with dilute bleach baths or chlorhexidine body washes daily, each for 5 days per month. Nonetheless, recurrent infections still occur in over 30% of patients after 4 months of eradication.57 For a history of four or more episodes of furunculosis, nasal application of mupirocin for 5 days, chlorhexidine disinfection daily for 21 days, and oral clindamycin for 21 days is 87% effective for preventing recurrence.58 Data regarding the efficacy of nasal mupirocin in reducing the overall rate nosocomial S. aureus infections have been conflicting.59,60 A large trial found that intranasal mupirocin, in combination with chlorhexidine soap, reduced nosocomial S. aureus surgical-site infections from 7.7% to 3.4% in nasal carriers.61 Q41.2 Among nasal MRSA carriers undergoing Mohs surgery, no postoperative MRSA infections occurred in patients who used intranasal mupirocin and trimethoprim/sulfamethoxazole for 5 to 7 days.62 Q41.6 In children and adults with atopic dermatitis, S. aureus colonization is very frequent and is a risk factor for exacerbations

of disease or recurrent S. aureus infections.63,64 Furthermore, S. aureus colonization is directly proportional to disease severity. Colonization occurs in lesional and nonlesional skin,65 and up to 65% of lesional strains of S. aureus produce superantigenic exotoxins which can stimulate large numbers of T lymphocytes, provoking disease exacerbations.64 There is a high prevalence of MRSA and multidrug resistance among strains of S. aureus in pediatric patients with atopic dermatitis.63 In children with a superimposed bacterial infection, intermittent intranasal mupirocin, dilute bleach baths, and oral cephalexin reduced the severity of atopic dermatitis compared with cephalexin alone.66 In adults, treatment of skin and nasal S. aureus carriage with intranasal mupirocin, oral cephalexin, and chlorhexidine ointment also led to significant improvement in atopic dermatitis.64 In two studies, use of mupirocin ointment combined with a topical corticosteroid (CS) ointment (either hydrocortisone butyrate 0.1% or fluticasone 0.005%) reduced the severity of atopic dermatitis for 1 week, but this improvement was not sustained.65,67 More than 50% of patients with mycosis fungoides and Sézary syndrome have skin and/or nasal colonization with S. aureus, with erythrodermic patients affected most frequently. Intranasal mupirocin combined with oral antibacterial agents has produced clinical improvement in 58% of S. aureus-colonized patients in this demographic.68 The use of mupirocin for S. aureus decolonization in immunocompromised patients has also been studied. Monthly intranasal mupirocin for 8 consecutive months significantly reduced the rate of S. aureus colonization among human immunodeficiency virus (HIV)-positive patients in a long-term care setting, but did not affect the rate of S. aureus infection.69 In hemodialysis patients, intranasal mupirocin has been shown to reduce the incidence of S. aureus bacteremia, but serial retreatment may be necessary for sustained decolonization.70,71 Burns. In burn patients without baseline colonization, nasal mupirocin reduced the risk of acquiring S. aureus in burn wounds.72 Compared with silver sulfadiazine, silver nitrate, mafenide acetate, and honey, mupirocin was the most highly active topical antimicrobial against clinical isolates of MRSA recovered from burn wounds.73 In addition, twice-daily mupirocin under occlusion for fewer than 5 days was effective in eliminating MRSA in burn wounds encompassing > keratolytic effects for acne Beneficial effects can be ‘neutralized’ with simultaneous tretinoin Has not been associated with induction of bacterial resistance Rare potential for contact allergy

Clindamycin

Good Gram (+) and anaerobic bacterial coverage Antibiotic associated colitis very unlikely with topical use of clindamycin phosphate

Erythromycin

Resistance of some Propionibacterium acnes strains A significant component of long-term acne benefit through erythromycin anti-inflammatory effects

Metronidazole

Has coverage for both aerobic and anaerobic bacteria Also has some parasitic coverage—uncertain role of Demodex folliculorum in rosacea patients (see text)

Azelaic acid

Broad antimicrobial coverage, including P. acnes Also useful for certain disorders of pigmentation

Dapsone

Effective with rapid onset of action for inflammatory lesions No requirement for G6PD deficiency screening or monitoring of hematologic parameters

Sodium sulfacetamide

Available in several rosacea products in combination with precipitated sulfur

G6DP, Glucose-6-phosphate dehydrogenase.

TABLE Drugs Discussed in This Chapter—Topical Antibacterial Agents Used for Acne and Rosacea 41.8

Generic Name Benzoyl

peroxidea

Clindamycin phosphate (1%)

Trade Name

Manufacturer

Generic Available

Creamb Tube Sizes

Special Formulations

Various

Various

Yes

Various

Lotion—various sizes Gel—various sizes Solution—various sizes Soap bar—113 g

Cleocin T Lotion

Pharmacia Upjohn

Yes

Lotion—60 mL

Cleocin T Gel

Yes

Gel—30 g, 60 g

Cleocin T Solution

Yes

Solution—30 g, 60 mL

Erythromycinc

Various

Various

Yes

Gel—30 g, 60 g; 65 g pads—60/box Solution 60 mL, 120 mL

Metronidazole

Metrogel (0.75%, 1.0%)

Galderma

No/Yes

Gel—45 g

Metrocream (0.75%)

Galderma

Yes

45 g

Noritate (1%)

Dermik

No

30 g

Azelex (20%)

Allergan

No

30 g, 50 g

Finacea (15%)

Berlex

No

Dapsone

Aczone (5%/7.5%)

Allergan

Yes/No

Sodium and sulfurc

Various

Various

Yes

Various Various

Azelaic acid

Gel—40 g

Gel—30 g, 60 g Various

Lotion, solution, foam, pads

Various

Various

Lotion, solution, foam, pads

Various

Various

Lotion, solution, foam, pads

None of these topical antibiotics are available in ointment formulations. aFor full spectrum of benzoyl peroxide options see Table 41.5. bFor full spectrum of topical erythromycin options see Table 41.9. cNovacet, Klaron, Plexion, other trade names; Most commonly 5% sulfur/10% sulfacetamide, net most commonly 4.8% sulfur/9.8% sulfacetamide, others.

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TABLE Common Benzoyl Peroxide Formulations 41.9

Name

Manufacturer

Formulations

Sizes

Benzac

Galderma

5%, 10% gel

60 g

Benzac AC

Galderma

2.5%, 5%, 10% gel

60 g

Benzac W

Galderma

2.5%, 5%, 10% gel

60 g, 90 g

Benzagel

Dermik

5%, 10% gel

45 g, 90 g

Benzashave

Medicis

5%, 10% shaving cream

120 g

Brevoxyl

Stiefel

4% gel

42.5 g

Desquam—E

Westwood—Squibb

2.5%, 5%, 10% gel

45 g

Desquam—X

Westwood—Squibb

2.5% gel 5%, 10% gel

45 g 45 g, 90 g

PanOxyl

Stiefel

5%, 10% gel

60 g, 120 g

TABLE Pregnancy Categories of Agents Used for Acne 41.10 and Rosaceaa

Name

Pregnancy Category

Benzoyl peroxide

C

Clindamycin

B

Erythromycin

B

Metronidazole

B

Azelaic acid

B

Dapsone

C

Sodium sulfacetamide

C

aEditor’s

note (SEW) - refer to Chapter 65 for updated ratings on selected drugs in this and subsequent Pregnancy Category tables.

Adapalene 0.1%/BP 2.5% gel significantly reduced lesion counts with a faster onset of action (as early as 1 week) than either adapalene or BP alone in several studies.140–142 For severe inflammatory acne, the addition of once-daily adapalene 0.1%/BP 2.5% gel to 100 mg of oral doxycycline daily reduced all lesions after 12 weeks to a greater extent than doxycycline alone, and the earlier onset of action with combination therapy correlated with a rapid reduction in P. acnes in the first 4 weeks.143 Combination treatment with BP and topical tretinoin has been shown to be superior to monotherapy with either drug.144 BP 6% cleanser and tretinoin 0.1% microsphere gel reduced greater numbers of inflammatory and noninflammatory lesions than treatment with tretinoin 0.1% microsphere gel alone.145 Q41.11 Because BP may oxidize tretinoin if applied simultaneously, it is recommended that BP be used in the morning and tretinoin at night.127 However, an optimized, aqueous gel formulation of tretinoin may be combined with BP without risk of peroxide-induced degradation of tretinoin.146 Rosacea. Daily application of BP 5%/clindamycin 1% gel for 12 weeks significantly reduced papules and pustules and was well tolerated.147 Adverse Effects. The main AE of topical BP is an irritant dermatitis with symptoms of burning, erythema, peeling, and dryness.131,132 Twice-daily application of 2.5% BP is as effective as the

5% or 10% formulations, but with fewer AE.129 Water-based gels are less irritating than alcohol- or acetone-based formulations.127 Transient dryness and irritation is more frequent with adapalene 0.1%/BP 2.5% gel than with monotherapy with either agent,140 and the safety profile of this fixed-dose combination gel is similar to that of adapalene 0.1% gel alone.141 Adapalene 0.1%/BP 5% gel caused significantly more irritation than adapalene 0.1%/BP 2.5% gel, or BP 2.5%, 5%, or 10% gel monotherapy. However, adapalene 0.1%/BP 2.5% gel demonstrated a tolerability profile similar to that of BP 2.5% or 5% gel monotherapy.148,149 There is a 0.2% to 1% incidence of true contact allergy.150,151 Patch testing may be done with BP 5% gel (15% false-positive reactions) or with 2% BP in petrolatum (3% false-positive reactions) (see Table 41.4).151 Patients should be advised that the drug can bleach fabric, hair, and other colored materials.134 When the drug was first released there was concern for potential carcinogenesis because of its role as a tumor promoter in mice.152–154 However, subsequent human studies have not found any link between BP and skin cancer.153,155

Clindamycin Pharmacology

Clindamycin is a synthetic derivative of the antibacterial agent lincomycin, which is isolated from the Streptomyces species. For topical application, it is available as a 1% alcohol-based solution, 1% lotion, and 1% gel. Although all formulations are equally efficacious for the treatment of acne vulgaris, the lotion is less irritating, with fewer reports of dryness.156 Approximately 4% to 5% of the drug is systemically absorbed.157 Clindamycin is classified as pregnancy category B (see Table 41.10). Microbiologic Activity. The drug is a broad-spectrum antibacterial that functions by irreversibly binding to the 50s subunit of the bacterial ribosome.158 This inhibits bacterial protein synthesis and may produce bactericidal or bacteriostatic effects. The drug is effective against most aerobic Gram-positive cocci, with the exception of enterococcus species.159 It has classically been active against community-acquired MRSA (CA-MRSA), although resistance is increasing.158,159 Clindamycin also provides coverage against both Gram-positive and Gram-negative anaerobes, but has virtually no activity against aerobic Gram-negative bacteria.160–162 (see Table 41.6) Q41.12 Although clindamycin is effective against P. acnes,

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Topical Antibacterial Agents

475

TABLE Common Topical Combination Formulations 41.11

Name

Manufacturer

Formulations

Sizes

Acanya

Valeant

Clindamycin phosphate and benzoyl peroxide, 1.2%/5%

50 g

Aktipak

Cutanea Life Sciences

Erythromycin and benzoyl peroxide, 3%/5%

60 pouches

Benzaclin

Dermik

Clindamycin phosphate and benzoyl peroxide, 1%/5%

25 g, 50 g

Benzamycin Pak

Dermik

Erythromycin and benzoyl peroxide 3%/5%

23.3 g, 46.6 g

Duac

Stiefel

Clindamycin phosphate and benzoyl peroxide gel, 1.2%/5%

45 g

Epiduo

Galderma

Adapalene and benzoyl peroxide 0.1%/2.5%

45 g

Epiduo Forte

Galderma

Adapalene and benzoyl peroxide 0.3%/2.5%

15 g, 30 g, 45 g, 60 g, 70 g

Neuac

Medimetriks

Clindamycin phosphate and benzoyl peroxide gel, 1.2%/5%

45 g

Onexton

Valeant

Clindamycin phosphate and benzoyl peroxide gel, 1.2%/3.75%

50 g

Veltin

Stiefel

Clindamycin phosphate and tretinoin 1.2%/0.025%

30 g

Ziana

Cerner Multum

Clindamycin phosphate and tretinoin 1.2%/0.025%

30 g, 60 g

an increasing number of clindamycin-resistant strains are associated with treatment failure.160 BP 5% in combination with clindamycin 1% produces rapid, clinically significant reductions in P. acnes (including clindamycin-resistant strains) greater than those produced by clindamycin alone.160–162 Clinical Use Acne Vulgaris. The main indication for topical clindamycin is

the treatment of acne vulgaris. Topical clindamycin is no longer recommended as monotherapy: P. acnes resistance to topical clindamycin ranges from 18.8% to 91% depending on geographic location.125,163–165 Multiple studies have focused on topical clindamycin as part of combination regimens with BP, topical retinoids, or zinc. BP 5%/ clindamycin 1% gel demonstrated significant reductions in the number of total and inflammatory lesions compared with monotherapy (Table 41.11).166 Compared with once-daily adapalene 0.1%, once-daily clindamycin 1%/BP 5% demonstrated comparable overall results in mild to moderate acne, but clindamycin 1%/BP 5% had an earlier onset of action, was more effective against inflammatory lesions, and had fewer AE.167,168 In moderate to severe acne, clindamycin 1%/BP 5% gel in addition to tazarotene 0.1% cream produced significantly greater reductions in comedonal and inflammatory lesions than tazarotene 0.1% cream alone.169 Clindamycin-BP 1.2%/3.75% gel and clindamycin-BP 1.2%/2.5% gel were both found to be effective in severe acne with an apparent BP dose-dependent response.163 Clindamycin-BP 3.75% gel was better tolerated than adapalene 0.3%-BP 2.5% gel in moderate-to-severe acne.164 Finally, clindamycin 1%/BP 5% gel produced greater reductions in P. acnes in vivo than clindamycin 1.2%/tretinoin 0.025% gel, and only clindamycin 1%/BP 5% gel reduced clindamycin- and erythromycin-resistant strains of P. acnes.170 Of note, irritation caused by 5% preparations of BP may be limiting. A gel formulation of clindamycin 1.2%/BP 2.5%, free of alcohol or surfactants, was found to be effective and well tolerated in moderate to severe acne, but comparison studies against combinations with 5% BP are lacking.171,172

The addition of zinc acetate to topical clindamycin reduces systemic absorption of clindamycin.173 Clindamycin 1%/zinc acetate gel demonstrates efficacy and safety equivalent to that of clindamycin 1% lotion alone.174 Although high quality evidence is lacking, topical clindamycin has a long history of use for bacterial folliculitis.51 Topical clindamycin 1% twice daily for 2 to 3 weeks is also the historical treatment of choice for erythrasma.165 Clindamycin 1%-BP 5% gel was reported to be effective for pitted keratolysis.175 Adverse Effects. Mild local reactions include itching, burning, stinging, excessive dryness, peeling, oily skin, and erythema.128 These reactions are usually attributed to the vehicle.176 Contact allergy to clindamycin is very rare, even though use of the drug is widespread.177–181 Patch testing can be done with a 1% clindamycin suspension in water (see Table 41.4). Gram-negative folliculitis has rarely been associated with topical clindamycin use.182 Although extremely rare, antibiotic-associated (pseudomembranous) colitis has been reported in association with topical clindamycin.183,184

Erythromycin Pharmacology

Erythromycin is a macrolide antibacterial agent isolated from a strain of Streptomyces erythraeus.159 The drug is available in various vehicles and concentrations from 1% to 4%. To date, there are no published data on systemic absorption from topical erythromycin. Erythromycin is classified as pregnancy category B (see Table 41.10). Microbiologic Activity. The drug is bactericidal and inhibits bacterial protein synthesis by binding to the 50s subunit of the bacterial ribosome. The binding site is either identical to or very close to that of clindamycin. Erythromycin is effective against Gram-positive cocci, Corynebacterium, H. influenzae, Legionella pneumophila, Chlamydia spp, T. pallidum, Mycoplasma pneumoniae, and Ureaplasma urealyticum.158 (see Table 41.6) Q41.12 Up to 25% of antibiotic-treated acne patients harbor strains of erythromycin-resistant P. acnes, regardless of treatment history.185 Q41.13 One strategy to circumvent this problem is to use a higher

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TABLE 41.12 Common Topical Erythromycin Formulations

Name

Manufacturer

Formulations

Sizes

A/T/S

Hoechst Marion Roussel

2% solution 2% gel

60 mL 30 g

Benzamycin

Dermik

3% erythromycin plus 5% benzoyl peroxide gel

23.3 g, 46.6 g

Erycette

Ortho Dermatological

2% swabs

60/box

Erygel

Allergan

2% gel

30 g, 60 g, 65 g

Theramycin Z

Medicis

2% solution

60 mL

T-stat

Westwood-Squibb

2% solution 2% pads

60 mL 60/box

concentration of erythromycin: 4% erythromycin with or without 1.2% zinc is effective in reducing erythromycin-resistant P. acnes in vivo.186 In vitro, the addition of zinc salts also reduces resistance of P. acnes to erythromycin.187 Another tactic found effective in reducing erythromycin-resistant P. acnes is to use erythromycin in combination with BP.188 Clinical Use Acne Vulgaris. The main indication for topical erythromycin

is the treatment of acne vulgaris. Topical erythromycin is available in a variety of vehicles in concentrations of 2% and 3% (Table 41.12). Point mutations in the genes encoding the 23s subunit of ribosomal RNA lead to resistance to the macrolide– lincosamide–streptogramin B (MLS) antibiotics, accounting for the cross-resistance observed between erythromycin and clindamycin.123–125 In recent years, rates of resistance to erythromycin in P. acnes have ranged from 50% to 100%, depending on geographic location.123–125 Topical erythromycin is no longer recommended as monotherapy.125 Combination topical treatments with BP and erythromycin have been found to reduce inflammatory lesions as much as oral therapy with either oxytetracycline or minocycline in the treatment of mild-to-moderate acne. Unlike tetracycline regimens, BP/erythromycin combinations did not induce P. acnes resistance.189 Other Uses. A small study comparing erythromycin in combination with BP to metronidazole showed that erythromycin and BP may be an alternative choice for treatment of rosacea.190 Although there is no high-quality evidence to support its use, topical erythromycin 2% (twice daily for 2–3 weeks) is a first-line therapy for erythrasma165 and pitted keratolysis.191 Adverse Effects. In  vivo, mild symptoms such as erythema, scaling, tenderness, burning, itching, irritation, oiliness, and dryness have been reported.192,193 Erythromycin is a weak sensitizer194 and ACD has been infrequently reported.195–197 Patch testing can be done with erythromycin base 1% to 5% in petrolatum (see Table 41.4).

Metronidazole Pharmacology

Metronidazole is a synthetic nitroimidazole antibacterial readily taken up by anaerobic organisms. Inside these susceptible cells, reduction products of metronidazole result in DNA disruption

and inhibition of nucleic acid synthesis (see Table 41.6).198 For topical application, this drug is available in the United States as a 0.75% gel or cream and a 1% gel. When applied to skin, systemic absorption is negligible.199–201 Both oral and topical metronidazole are classified as pregnancy category B (see Table 41.10).159 Microbiologic Activity. Metronidazole is active against most anaerobic bacteria and protozoa, including Bacteroides fragilis, Bacteroides melaninogenicus, Fusobacterium spp, Veillonella spp, Clostridium spp, Peptococcus spp, Peptostreptococcus spp, Entamoeba histolytica, Trichomonas vaginalis, Giardia lamblia, and Balantidium coli.202 (see Table 41.6) Q41.14 This drug is not active against P. acnes, staphylococci, streptococci, fungi, or Demodex folliculorum.192,203 After 1 month of treatment, the skin microflora of topical metronidazole-treated patients were no different from those in untreated patients.204 In  vitro studies show that D. folliculorum can survive in as much as 1 mg/mL of metronidazole. Thus, it seems unlikely that the beneficial effect of metronidazole for rosacea stems from direct killing of the mite.205 Q41.14 The mechanism of action of metronidazole for the treatment of rosacea is uncertain, but metronidazole has antiinflammatory effects that include suppression of cell-mediated immunity and leukocyte chemotaxis.200 Clinical Use Rosacea. Clinical trials with metronidazole 0.75% topical gel

or 1% topical cream showed a reduction of inflammatory lesions in 68% to 96% of patients.198,206 In patients with moderate rosacea, twice-daily 0.75% metronidazole gel resulted in a 51% to 65% reduction of papules and pustules after 9 weeks of use; erythema was also reduced.185,207 Compared with adapalene 0.1% gel, metronidazole 0.75% gel was more effective in reducing erythema, but less effective in reducing the total number of inflammatory lesions.208 The combination of metronidazole 1% cream and sunscreen with sun protection factor (SPF) 15 produced greater improvement in erythema, telangiectasias, and inflammatory lesion counts than sunscreen with SPF 15 alone.209 Trials have shown that the efficacy of metronidazole 0.75% lotion or 1% gel is enhanced by the addition of anti-inflammatory (subantimicrobial) doses of doxycycline (40 mg daily).210,211 Metronidazole is effective against pustules, papules, and to a lesser degree erythema. However, it is generally ineffective against telangiectasias and rhinophyma.212 Previous experience has shown that this drug does not improve the ocular effects of rosacea,

CHAPTER 41

although it is useful for rosacea lid blepharitis.213 Topical metronidazole can be effective for severe and recalcitrant rosacea.214 The 1% metronidazole cream has been shown to be as effective as oral tetracycline.215 Acne Vulgaris. Topical metronidazole does not have a significant role in the treatment of acne vulgaris. Although 2% metronidazole with 5% BP demonstrated an improvement over BP alone and placebo,216 0.75% metronidazole gel alone had no beneficial effect.217 Cutaneous Ulcers. Several studies have demonstrated that topical metronidazole can be used to eliminate the odor of putridsmelling ulcers as well as ulcerated or fungating tumors.218–223 In a small series of sacral decubitus ulcers treated with metronidazole gel, elimination of odor correlated with negative anaerobic cultures and Wood’s light examination after treatment.224 Compared with placebo, metronidazole 10% ointment significantly reduced pain and discharge in patients with perianal Crohn disease.225,226 Seborrheic Dermatitis. Q41.15 Metronidazole 1% gel is more effective than placebo in reducing the severity of seborrheic dermatitis. Of note, metronidazole 0.75% gel, ketoconazole 2% cream, and placebo, are equally effective for seborrheic dermatitis.227–231 Adverse Effects. AE of topical metronidazole are rare and include dryness, itching, burning, and stinging. Topical metronidazole has a very low potential for causing sensitization,232 but several cases of ACD have been documented233,234 (see Table 41.4). Patch testing can be done with 1% metronidazole in petrolatum. Cases of contact allergy to tioconazole and isothiazolinones with cross-reactivity to metronidazole have been reported.235,236

Azelaic Acid Pharmacology

Azelaic acid is a naturally occurring saturated 9-carbon dicarboxylic acid. Dicarboxylic acids produced in tinea versicolor infection are competitive inhibitors of tyrosinase,237 a property that has suggested the use of azelaic acid in pigmentary disorders. Azelaic acid suppresses ultraviolet B light-induced expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α messenger RNA through interaction with the peroxisome proliferators-activated receptor γ (PPARγ), suggesting a mechanism for this agent’s effect in rosacea.238 The percentage of topical dose absorbed is calculated to be about 3%. A 15% gel has been shown to result in absorption (8%) higher than that of the 20% cream (3%).239 In the United States, azelaic acid is available as a 20% cream (Azelex) and a 15% gel (Finacea). Azelaic acid is classified as pregnancy category B (see Table 41.10). Microbiologic Activity. The antimicrobial activity of azelaic acid is attributable to inhibition of protein synthesis in susceptible organisms. The exact mechanism of action is unclear. In  vitro, azelaic acid is bacteriostatic against S. epidermidis, S. aureus, Staphylococcus capitis, Staphylococcus hominis, P. acnes, Propionibacterium granulosum, Propionibacterium avidum, P. mirabilis, E. coli, P. aeruginosa, and C. albicans.240 In  vitro activity against bacteria is enhanced under nutrient depletion and low pH; the latter factor favors uptake of azelaic acid into the cell.241 (see Table 41.6) Clinical Use Acne Vulgaris. Azelaic acid is indicated for the treatment of

acne and reduces the concentration of P. acnes on the skin surface and follicles.242,243 Azelaic acid inhibits the division and differentiation of human keratinocytes, but does not reduce the rate of sebum production.244 Nevertheless, patients often report gradual reduction in skin greasiness after 1 to 2 months of treatment.245,246

Topical Antibacterial Agents

477

Higher penetration into lesions may be achieved by applying the cream 3 to 4 times daily.247 Improvement in acne is detectable after 1 to 2 months242,248 and is maximal after 4 months.248,249 Azelaic acid is more effective than placebo,242,249 and is comparable to topical 0.05% tretinoin cream,249 topical 5% BP,250 topical 2% erythromycin cream,240 and even oral tetracycline243,248 in the treatment of mild-to-moderate acne. The combination of azelaic acid 5% and erythromycin 2% gel is more effective than placebo, erythromycin 2% alone, or azelaic acid 20% alone, with fewer AE than monotherapy.251 Rosacea and Perioral Dermatitis. Azelaic acid 15% gel twice daily for 15 weeks was superior to 0.75% metronidazole gel in improving the inflammatory lesions and erythema of rosacea.252 Azelaic acid 20% cream has been shown to be an effective and safe alternative to metronidazole 0.75% cream.253,254 Once-daily metronidazole 1% gel and twice-daily azelaic acid 15% gel showed comparable efficacy in the treatment of moderate rosacea.255 Efficacy was also similar between regimens using oral doxycycline 40 mg once daily in combination with either once-daily metronidazole 1% gel or with twice-daily azelaic acid 15% gel.256 Twicedaily application of azelaic acid 20% cream led to clearance of lesions in pediatric patients with CS-induced, nongranulomatous perioral dermatitis after 4 to 8 weeks.257,258 Plaque Psoriasis. Azelaic acid 15% gel was significantly more effective than vehicle gel in the reduction of body surface area involvement, total Psoriasis Area Severity Index (PASI) score, scaling, and hyperkeratosis.259 Disorders of Pigmentation. Azelaic acid has no depigmenting activity on normal skin, solar freckles, senile freckles, lentigines, pigmented seborrheic keratoses, or nevi.240 Azelaic acid has some activity against hypermelanosis caused by physical and chemical agents, postinflammatory hyperpigmentation, melasma, lentigo maligna, and lentigo maligna melanoma.240,241,247 In melasma, treatment for 24 weeks with azelaic acid 20% cream alone showed similar efficacy to treatment for 8 weeks with clobetasol 0.05% cream followed by 16 weeks with azelaic acid 20% cream (90% vs. 96.7% improvement).260 Adverse Effects. Azelaic acid is nontoxic, nonmutagenic, and nonteratogenic in animal models.261–263 In humans, azelaic acid was considered as a potential energy substrate, and parenteral infusion resulted in no AE.261 To date, there have been no cases of contact allergy to azelaic acid. Up to 10% of patients may report itching, burning, or scaling, which may last up to 4 weeks. Local reactions may be reduced by initiating treatment with once-daily application during the first 1 to 2 weeks of treatment.264

Dapsone Pharmacology

Dapsone (4,4’-diaminodiphenyl sulfone) is an antimicrobial and anti-inflammatory agent that is FDA-approved (oral formulation) for the treatment of leprosy and dermatitis herpetiformis. Dapsone has a history in the successful treatment of neutrophilic dermatoses.265 Briefly, dapsone interferes with neutrophilic function through multiple mechanisms,266–274 including inhibition of IL-8 release.275 Neutrophil myeloperoxidase inhibition is also relevant to the drug’s efficacy. In addition, dapsone suppresses production of TNF-α by activated mononuclear cells, suggesting its mechanism in the treatment of cutaneous lupus.276 A topical gel formulation of dapsone 5% (Aczone) is FDAapproved for the treatment of acne vulgaris. Twice-daily application to 22.5% body surface area for 2 weeks resulted in a

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steady-state systemic absorption 126 times lower than that achieved with a single 100 mg oral dose. During treatment for 1 year, drug levels did not increase, and total systemic exposure to dapsone and its metabolites was 100 times lower for dapsone gel than for oral dapsone.277 Following absorption, dapsone undergoes N-acetylation and N-hydroxylation in the liver; excretion is renal, with significant enterohepatic circulation.278 The half-life of topical dapsone is 48 hours versus 20.6 hours for oral dapsone.277 Both the topical and oral formulations are classified as pregnancy category C (see Table 41.10). Microbiologic Activity. In vivo, dapsone demonstrates activity against Mycobacterium leprae.279 In vitro, multiple other Mycobacterium species are sensitive to dapsone, including M. avium, M. intracellulare, M. kansasii, M. fortuitum, M. ulcerans, and M. tuberculosis.280,281 Additionally, dapsone shows in vitro antimicrobial activity against Pneumocystis jirovecii (previously P. carinii),282 Plasmodium falciparum,283 Leishmania major,284 and Toxoplasma gondii.285 The antimicrobial activity of dapsone results from its inhibition of dihydropteroate synthetase, an enzyme that reduces folic acid.283(see Table 41.6) Clinical Use Dermatologic Uses. Twice-daily dapsone 5% gel was more effec-

tive than vehicle in reducing inflammatory lesion counts within 2 weeks.286 Similar long-term efficacy was demonstrated: at 12 months, mean reduction from baseline inflammatory, noninflammatory, and total lesion counts was 58.2%, 19.5%, and 49%, respectively, confirming the greater efficacy of dapsone gel in treating inflammatory lesions of acne.287 A randomized trial comparing twice-daily dapsone 5% gel monotherapy to combination regimens with once-daily BP 4% gel and once-daily adapalene 0.1% gel found no significant difference in the reduction of inflammatory lesions. However, in combination regimens, particularly with adapalene 0.1%, dapsone 5% gel demonstrated a greater reduction in noninflammatory and total lesion counts than topical dapsone alone.288 Adverse Effects. The most commonly reported AE are transient dryness, erythema, rash, or sunburn.286,287 Q41.16 Patients with G6PD deficiency are more sensitive to developing hemolysis following exposure to oxidative stressors289 such as the hydroxylamine metabolite of dapsone, which is responsible for dose-related hemolytic anemia and methemoglobinemia.290 No significant changes in hemoglobin levels occurred among patients with G6PD deficiency in the pivotal long-term safety studies.286,287 Twice-daily application of dapsone 5% gel for 2 weeks in patients with G6PD deficiency resulted in a transient decrease of 0.32 g/ dL from baseline hemoglobin levels, although clinical signs or symptoms of hemolytic anemia were absent. No other changes in laboratory markers of hemolysis occurred.291 There is no requirement for G6PD screening before or monitoring of hematologic parameters during treatment with topical dapsone.292 Sulfones such as dapsone are structurally distinct from sulfonamides such as sulfamethoxazole.293 Although both drugs contain arylamine groups targeted in hypersensitivity reactions, cross-reactivity between the two classes is uncommon. Patients with a preexisting sulfonamide allergy are at no greater risk for allergic reactions caused by sulfones than allergies caused by penicillin.294 In clinical trials, no hypersensitivity reactions to topical dapsone were observed.286,287 Thus, there is little evidence to suggest an increased risk of hypersensitivity to topical dapsone conferred by pre-existing sulfonamide allergy.293 When mixed with BP, dapsone may produce an orange-brown discoloration that stains clothing, but not skin.295

TABLE 41.13 Key Concepts—Common Topical Antiseptics

Name

Comments

Triclosan

Primary antibacterial soap ingredient available today; recently banned in healthcare products Active ingredient in Dial, pHisoderm, Safeguard, Softsoap, others

Chlorhexidine

Primarily used as a surgical scrub Active ingredient in Hibiclens Also in liquid hand cleansers, toothpastes, contact lens care products

Povidone-iodine

Primarily used as a surgical scrub Active ingredient in Betadine solution

Sodium Sulfacetamide Sodium sulfacetamide possesses antibacterial and anti-inflammatory properties, and is incorporated in a formulation with sulfur, a nonspecific antifungal and antibacterial, for use in the treatment of acne and rosacea296 Sulfacetamide inhibits bacterial dihydropteroate synthetase, preventing the conversion of p-aminobenzoic acid (PABA) into folic acid297 (see Table 41.6). Sodium sulfacetamide is classified as pregnancy category C (see Table 41.10). One 12-week study showed a 78% decrease in total acne lesion count and an 83% decrease in inflammatory lesion count.298 Compared with metronidazole 0.75% cream, combination treatment with sodium sulfacetamide 10%/sulfur 5% cream and sunscreens for 12 weeks resulted in a greater reduction in inflammatory lesions (72% vs. 80%) and erythema (45% vs. 69%) in rosacea.299 Common AE include mild-to-moderate dryness and transient pruritus in over half of patients.298 When combined with topical preparations containing BP, sulfacetamide produces an orangebrown discoloration, which does not stain skin, but may stain clothing.295

Antiseptics Antiseptics are most commonly used for surgical skin sterilization and for personal hygiene. They are found in products such as skin care preparations, mouthwashes, and toothpastes. They have a broad antimicrobial spectrum with a low incidence of irritation or ACD (Table 41.13).

Triclosan Triclosan (sodium 5-chloro-2-(2,4-dichlorophenoxy)phenol fluoride) is a broad-spectrum agent currently found in many personal care products such as deodorants, toothpaste, mouth rinses, and hand washes.300–302 Recent studies have shown that repeated exposure to triclosan is associated with increased risk of bacterial resistance, specifically in S. aureus and E. coli species.300–302 For this reason, the FDA banned the use of triclosan in products, including antiseptics available over the counter (OTC) intended for use in a healthcare setting, as of December 21, 2018. Of note, this ban does not address products available for public consumption.300–302

CHAPTER 41

Chlorhexidine Chlorhexidine (1,1-hexamethylenebis[5-(P-chlorophenyl) biguanide]) is an antimicrobial agent that has broad-spectrum coverage, including S. aureus, P. aeruginosa, S. marcescens, and facultative anaerobes.303 As noted above, chlorhexidine body washes as part of combination regimens are useful for reducing the rate of recurrent S. aureus pyoderma and furunculosis in immunocompetent hosts.57,58 Preoperative cleansing with chlorhexidine-alcohol was more effective than povidone-iodine in preventing superficial incisional infections (4.2% vs. 8.6%) and deep incisional infections (1% vs. 3%) within the first 30 days after surgery.304 ACD caused by chlorhexidine is rare,305 but sensitization to chlorhexidine has been reported in up to 42.5% of children with atopic dermatitis.306 Patch testing is usually performed with a 1% aqueous solution of chlorhexidine gluconate.307 More than 50 cases of anaphylaxis attributed to chlorhexidine have been reported in the literature, but only 2 cases have resulted from application to intact skin.308 Q41.17 When using chlorhexidine for skin sterilization near the ear it is prudent to ensure that none of the disinfectant trickles into the ear, as chlorhexidine has been associated with ototoxicity resulting in deafness.309

Povidone-Iodine Povidone-iodine is an antimicrobial agent active against Grampositive and Gram-negative bacteria. It is commonly used as an antiseptic perioperatively and for skin wounds.310 Surgery involving the feet is complicated by high rates of infection, and the addition of 70% isopropyl alcohol to 7.5% to 10% povidone-iodine was more effective than 4% chlorhexidine in reducing the bacterial load from the first web space of normal feet.311 The incidence of ACD is rare.312 However, irritant contact dermatitis with tissue necrosis has resulted from prolonged contact with large quantities of povidone-iodine.310 Cases of irritant contact dermatitis resembling vasculitis313 and toxic epidermal necrolysis314 have also been reported. The recent FDA ruling

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discussed above also listed povidone-iodine as one of six ingredients that would require further study to address efficacy and safety in healthcare.300

References* 12. Zug KA, Warshaw EM, Fowler JF, et  al. Patch-test results of the North American Contact Dermatitis Group 2005-2006. Dermatitis. 2009;20:149– 160. 47. Patel JB, Gorwitz RJ, Jernigan JA. Mupirocin resistance. Clin Infect Dis. 2009;49:935–941. 89. Parish LC, Jorizzo JL, Breton JJ, et al. Topical retapamulin ointment (1%, wt/wt) twice daily for 5 days versus oral cephalexin twice daily for 10 days in the treatment of secondarily infected dermatitis: results of a randomized controlled trial. J Am Acad Dermatol. 2006;55:1003–1013. 108. Miller AC, Rashid RM, Falzon L, Elamin EM, Zehtabchi S. Silver sulfadiazine for the treatment of partial-thickness burns and venous stasis ulcers. J Am Acad Dermatol. 2010;66(5):e159–e165. 101. Campbell RM, Perlis CS, Fisher E, Gloster Jr HM. Gentamicin ointment versus petrolatum for management of auricular wounds. Dermatol Surg. 2005;31:664–669. 123. Adler L, Kornmehl H, Armstrong AW. Antibiotic resistance in acne treatment. JAMA Dermatol. 2017;153(8):810–811. 125. Zaenglein AL Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945–973. 140. Gollnick HP, Draelos Z, Glenn MJ, et al. Adapalene-benzoyl peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients. Br J Dermatol. 2009;161:1180–1189. 141. Thiboutot DM, Weiss J, Bucko A, et  al. Adapalene-benzoyl peroxide, a fixed-dose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study. J Am Acad Dermatol. 2007;57:791–799. 171. Gold MH. A new, once-daily, optimized, fixed combination of clindamycin phosphate 1.2% and low-concentration benzoyl peroxide 2.5% gel for the treatment of moderate-to-severe acne. J Clin Aesthet Dermatol. 2009;2: 44–48.

*Only a selection of references are printed here. All other references in the reference list are available online at www.expertconsult.com.

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42 Topical Antifungal Agents ADITYA K. GUPTA, RACHEL R. MAYS AND KELLY A. FOLEY

QUESTIONS Q42.1 What are primary examples of topical antifungal agents from the following categories: (1) polyenes, (2) azoles, (3) allylamines, (4) benzylamines, and (5) hydroxypyridones? (Pg. 480, Table 42.1) Q42.2 Although azole and allylamine antifungals both block ergosterol synthesis, how do they differ in their mechanism of action? (Pgs. 481, 486, Table 42.2) Q42.3 How does tavaborole differ from other antifungals in its mechanism of action? (Pg. 486, Table 42.2) Q42.4 What is the mechanism of action for ciclopirox olamine as an antifungal agent? (Pg. 487) Q42.5 How do terbinafine and naftifine compare in dermatophyte activity in vitro? (Pg. 488x2)

Q42.6 Which group of antifungal agents demonstrates the most potent in vitro and clinical activity against dermatophytes? (Pg. 489) Q42.7 Based on in vitro and clinical data, are the azole antifungals or the allylamine antifungals more efficacious for cutaneous candidiasis? (Pg. 490x2) Q42.8 Which class of topical antifungal agents possesses the most potent anti-inflammatory activity? (Pg. 490) Q42.9 Which class of topical antifungal agents has the most significant and most varied antibacterial activity? (Pg. 491) Q42.10 What are the pros and cons of treating vulvovaginal candidiasis during pregnancy with topical azole products? (Pg. 491)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R AE Adverse effect/event HETE Hydroxyeicosatetraenoic (acid) KOH Potassium Hydroxide MFC Minimum fungicidal concentration

Introduction Fungal infections are among the most common diseases of the skin and, taken all together, are second only to acne as the most common condition prompting dermatologic care. Topical antifungals (Fig. 42.1) are generally considered first-line therapy for uncomplicated, superficial dermatomycoses owing to their high efficacy and low potential for systemic adverse effects (AE). In the 1830s, Robert Remak and Johann Schonlein first identified fungi as the etiologic agent of human dermatomycoses and revealed the infectious nature of these microorganisms.1 David Gruby and Raimond Sabouraud, two influential mycologists, later published extensive research on the clinical, microscopic, and culture techniques relating to fungi that cause human disease. These developments marked the beginning of scientific medical mycology. Effective therapies for human dermatomycoses were slow to evolve, and it was not until 100 years after Remak and Schonlein’s initial findings that the first treatments demonstrating specific antimycotic actions were developed.1,2 480

MIC Minimum inhibitory concentration PMN Polymorphonuclear neutrophil UVB Ultraviolet B

World War II marked a pivotal point in the development of antifungal medications. Before the 1940s, antifungal therapy was limited to Castellini’s paint, Whitfield’s ointment, and Gentian violet. These nonspecific agents were generally irritating, staining, and minimally effective.2,3 The explosive increase in fungal infections, and recurring treatment failures during World War II, led to a more aggressive search for improved therapeutic measures and prompted the development of new training facilities, research institutions, and federal agencies specializing in medical mycology.1,2,4 There are now multiple modern topical antifungal agents capable of achieving clinical and mycologic eradication of human dermatomycoses. Q42.1 The most commonly employed topical antifungal agents belong to three main classes: (1) polyenes, (2) azoles, and (3) allylamines/benzylamines. Other topical antifungal agents, not among these major drug classes, include the hydroxypyridone antifungal agent ciclopirox olamine, the oxaborole antifungal tavaborole, and selenium sulfide (Table 42.1). Properties of these various classes are summarized in Table 42.2.

CHAPTER 42

Topical Antifungal Agents

481

Terbinafine Naftifine N

N

H

Tavaborole

H F H

C

H O

C B O CI

CI

H

N

Efinaconazole N

N H

O O H

N N

F

CI

N

Miconazole

F

CI

• Fig. 42.1

Chemical structure of topical antifungal agents (naftifine, terbinafine, tavaborole, miconazole, efinaconazole).

Polyenes Developed in the late 1950s, polyene antifungal agents were the first agents to have specific antifungal properties. Polyene antifungals are characterized by a macrolide ring of carbon atoms containing a number of conjugated double bonds (C=C–C=C), hence the name polyene.5–7 The polyene macrolide ring is closed by an internal ester or lactose.5 The two clinically significant and readily available polyenes are nystatin and amphotericin B. Only nystatin is covered in this chapter.

Nystatin Nystatin (Mycostatin, Mytrex, Nystop) was the first specific antimycotic to become available for human use and was discovered in 1949 by Hazen and Brown in the New York State Health Laboratory, hence the name, nystatin.8,9 Pharmacology

Nystatin is a polyene antibiotic produced by Streptomyces noursei and Streptomyces albidus.8,9 It is a tetraene antibiotic with both a conjugated diene and a conjugated tetraene moiety in the molecule. It also contains a sugar moiety, mycosamine, as part of its composition.5,7 It has a structure and mode of action similar to that of amphotericin B but associated systemic toxicity has limited nystatin’s use to topical applications. Nystatin is essentially insoluble in water and not absorbed from intact skin, the gastrointestinal tract, or the vagina. Mechanism of Action. Nystatin is an antifungal agent with both fungistatic and fungicidal activity in vitro. It acts by binding

irreversibly to membrane sterols of susceptible species of Candida, resulting in a change in membrane permeability and the subsequent leakage of essential intracellular components5,10,11 (see Table 42.2). Clinical Use Indications. Nystatin is a topical antifungal agent that is clini-

cally and mycologically effective in the treatment of cutaneous or mucocutaneous mycotic infections caused by Candida albicans and other susceptible candidal species; however, nystatin is clinically ineffective in the treatment of dermatophyte infections. Nystatin shows no appreciable activity against bacteria, protozoa, or viruses.5,12 Nystatin is available in cream, ointment, and powder formulations for twice-daily cutaneous application. Nystatin is also available in suspension and slowly dissolving pastille formulations for the treatment of oral candidiasis (thrush). Four to five times daily use is recommended in the latter situation. Adverse Effects. Nystatin is well tolerated by patients, with ciclopirox = naftifine > azoles. Clinical Trials. Controlled clinical trials have compared the efficacy of the various allylamine/benzylamine-type drugs with the azole antifungal agents. In a multicenter, double-blind parallelgroup study of 256 patients with mycologically confirmed tinea, Evans157 found that a 1-week course of terbinafine 1% cream was more effective than a 4-week course of clotrimazole 1% cream in the treatment of tinea pedis. By week 4, mycological cure was achieved in 93.5% of patients treated with terbinafine, compared with only 73.1% of patients treated with clotrimazole. In a multicenter comparison trial by Bergstresser and coworkers,158 results of mycological tests and clinical findings showed topical terbinafine to be significantly more effective than clotrimazole in the treatment of tinea pedis. Patients with mycologically proven tinea pedis were treated with either 1 to 4 weeks of topical terbinafine or 1 to 4 weeks of topical clotrimazole. At the end of week 12, 81% of the patients who had received 1 week of terbinafine were mycologically clear, whereas only 30% of the patients who received 1 week of clotrimazole cleared. In this study, 68% of those patients who received 4 weeks of clotrimazole had negative fungal cultures at week 12, whereas 85% of the patients

CHAPTER 42

Topical Antifungal Agents

489

TABLE Minimum Inhibitory Concentrations of Antifungal Agents Activity Against Dermatophytes (Mean mg/mL) 42.3

Fungus (# of strains)

Terbinafine

Naftifine

Ketoconazole

Trichophyton species (13)

50 g weekly)

For short-term use only, ideally 2–3 weeks at a time

Do not use on the face, axillae, submammary area or groin

Avoid use in infants and children under 12 years

Best for thick, lichenified or hypertrophic skin; avoid with thin skin

High (II & III)

Severe

Avoid extensive application (>50 g weekly)

For short-term use only, ideally 2–3 weeks at a time

Do not use on the face, axillae, submammary area or groin

Avoid use in infants and children under 12 years

Best for thick, lichenified or hypertrophic skin; avoid with thin skin

Intermediate (IV & V)

Moderate

Best for short-term treatment of extensive dermatoses

Avoid extended use (>1–2 weeks) in infants and children

Best on trunk and extremities

Avoid extended use (>1–2 weeks) in infants and children

Safer for shortterm use on thin skin; less effective on thicker skin

Low (VI & VII)

Steroid sensitive

Preferred for treatment of large areas

Best if long-term treatment is required

Best choice for face, axilla, groin, and other moist, occluded areas

Infants and children OK

Best for thin skin; not effective on thicker skin

TCS, Topical corticosteroid.

TABLE Considerations for Choosing a Vehicle for the Topical Corticosteroid 45.4

Preferred Dermatoses or Site of Use

Preferred Location of Use

Preparation

Composition

Skin Hydration Versus Drying

Cosmesis

Potential for Irritation

Ointment

Water in oil emulsion

Very good skin hydration

Best for thick, lichenified, or scaly dermatoses

Best for thick palmar or plantar skin; avoid with naturally occluded areas

Very greasy

Generally low

Cream

Oil-in-water emulsion

Moderate in skin hydrations potential

Best for acute, subacute or weeping dermatoses

Good for moist skin and intertriginous areas

Elegant

Variable; require preservatives

Gel

Cellulose cut with alcohol or acetone

Drying

Scalp or dermatoses in dense hair areas

Best for naturally occluded areas, scalp, and mucosa

Elegant

Higher

Lotion

Oil in water

Drying

Scalp or dermatoses in dense hair areas

Best for naturally occluded areas and scalp

Elegant

Higher

Solution

Alcohol

Drying

Scalp or dermatoses in dense hair areas

Best for naturally occluded areas and scalp

Elegant

Higher

antifungals may alter the stability213 or solubility of the CS or cause contact allergy. Urea 10% has been shown to cause significant degradation of the TCS in Topicort, Kenalog (discontinued brand of triamcinolone acetonide), and Westcort (discontinued brand of hydrocortisone valerate) creams.214 No such degradation of TCS occurred with 0.25% menthol,

camphor, or phenol; 2% salicylic acid; or 5% liquor carbonis detergens. Supervising Topical Corticosteroid Therapy. Like most prescription drugs, TCS therapy requires supervision to optimize benefits and minimize AE. The most effective form of supervision is the follow-up visit. Unfortunately, recent healthcare trends are

524

PA RT I X

Topical Immunomodulatory Drugs

TABLE 45.5 World Health Organization Potency Group and Class of Common Topical Corticosteroids

Generic Name

Common Brand Name(s), and Vehicle(s)

Superpotent, Class I Betamethasone dipropionate 0.05% (BDOV)

Diprolene ointment

Clobetasol propionate 0.05%

Clobex spray, shampoo, lotion Cormax solution, cream Olux E Foam, Olux Foam

Desoximetasone 0.25%

Topicort cream, gel, ointment, spray

Fluocinonide 0.1%

Vanos cream

Flurandrenolide tape 4 µg/cm2

Cordran tape

Halobetasol propionate 0.05%

Ultravate lotion, cream, ointment

Highly Potent, Class II Betamethasone dipropionate 0.05%

Diprolene cream

Desoximetasone 0.25%

Topicort cream, ointment

Desoximetasone 0.05%

Topicort gel

Fluocinonide 0.05%

Lidex solution, ointment

Halcinonide 0.1%

Halog cream, ointment

Mometasone furoate 0.1%

Elocon ointment

Triamcinolone acetonide 0.5%

Generic only ointment

Highly Potent, Class III Betamethasone valerate 0.1%

Betaval ointment

Betamethasone valerate 0.12%

Luxiq foam

Fluticasone propionate 0.005%

Cutivate ointment

Triamcinolone acetonide 0.1%

Generic only ointment

Triamcinolone acetonide 0.5%

Triderm cream

Moderately Potent, Class IV Desoximetasone 0.05%

Topicort LP cream, ointment

Fluocinolone acetonide 0.025%

Synalar ointment

Flurandrenolide 0.05%

Cordran ointment

Hydrocortisone valerate 0.2%

Westcort ointment

Mometasone furoate 0.1%

Elocon lotion, cream

Triamcinolone acetonide 0.1%

Triderm cream, generic paste

Moderately Potent, Class V Betamethasone valerate 0.1%

Betaval cream, generic lotion

Clocortolone pivalate 0.1%

Cloderm cream

Fluocinolone acetonide 0.03%

Synalar cream

Fluocinolone acetonide 0.01%

Capex shampoo

Fluticasone propionate 0.05%

Cutivate lotion, cream

Flurandrenolide 0.05%

Cordran lotion, cream

Hydrocortisone butyrate 0.1%

Locoid solution, lotion, cream, ointment

Hydrocortisone probutate 0.1%

Pandel cream

TABLE World Health Organization Potency Group and Class of Common Topical Corticosteroids—cont’d 45.5

Generic Name

Common Brand Name(s), and Vehicle(s)

Hydrocortisone valerate 0.2%

Generic only cream

Prednicarbate 0.1%

Dermatop cream, ointment

Low Potency, Class VI Alclometasone dipropionate 0.05%

Generic cream, ointment

Desonide 0.05%

DesOwen lotion, cream, ointment Desonate gel Verdeso foam

Fluocinolone acetonide 0.01%

Derma-Smoothe/FS oil

Triamcinolone acetonide 0.025%

Triderm cream

Low Potency, Class VII Dexamethasone sodium phosphate 0.1%

Generic only cream

Hydrocortisone acetate 2.5%

Micort-HC cream

Hydrocortisone acetate 0.5%–2.5%

Generic solution, lotion, cream, gel, ointment

TABLE 45.6 Topical Corticosteroid Products with Multiple Concentrations Available

Vehicle

Generic Product Name

Lower Strength (%)

Middle Strength (%)

Higher Strength (%)

Cream

Hydrocortisone

0.5

1.0

2.5

Fluocinolone acetonide

0.01

Triamcinolone acetonide

0.025

Flurandrenolide

0.01

0.025

Desoximetasone

0.1

0.25

Hydrocortisone

0.5

Flurandrenolide

0.01

Triamcinolone acetonide

0.025

0.1

0.5

Hydrocortisone

0.5

1.0

2.5

Triamcinolone acetonide

0.025

0.1

Hydrocortisone

1.0

2.0

Ointment

Lotion

Gel

0.025 0.1

1.0

0.5

2.5 0.025

‘Lower’, ‘middle’, and ‘higher’ in reference to ‘strength’ refers to comparison of the two or three strengths only; is not synonymous with potency in Stoughton vasoconstriction assay.

TABLE Estimating the Necessary Amount of Topical Corticosteroid for Adults 45.7

Anatomical Area

# of FTU Required To Cover

Amount for BID Application (g)

Amount for 1 Week of BID Application (g)

Amount for 4 Weeks of BID Application (g)

Face and neck

2.5

2.5

17.5

70

Anterior or posterior trunk

7

7

49

196

Arm

3

3

21

84

Hand (both sides)

1

1

7

28

Leg

6

6

42

168

Foot

2

2

14

56

BID, Twice a day; FTU, fingertip unit. Modified from Long CC, Finlay AY. The fingertip unit—a new practical measure. Clin Exp Dermatol. 1991;16(6):444–447.

526 PART IX

ANATOMICAL AREA

# OF FTU REQUIRED TO COVER

AMOUNT 1 WEEK OF BID APPLICATION (g)

AMOUNT BID APPLICATION (g)

Patient age range

3–6 mos

1–2 yrs

3–5 yrs

6–10 yrs

3–6 mos

1–2 yrs

3–5 yrs

6–10 yrs

3–6 mos 1–2 yrs 3–5 yrs 6–10 yrs

Face and neck

1.0

1.5

1.5

2.5

1.0

1.5

1.5

2.5

7.0

10.5

10.5

Arm and hand

1.5

1.5

2.5

3.0

1.5

1.5

2.5

3.0

10.5

10.5

Leg and foot

1.5

2.5

3.5

4.5

1.5

2.5

3.5

4.5

10.5

Anterior trunk

1.5

2.5

3.5

4.5

1.5

2.5

3.5

4.5

Posterior trunk 1.5 and buttocks

3.5

4.5

5.5

1.5

3.5

4.5

5.5

BID, Twice daily; FTU, fingertip unit. Modified from Long CC, Mills CM, Finlay AY. A practical guide to topical therapy in children. Br J Dermatol. 1998;138(2):293–296.

AMOUNT 4 WEEK OF BID APPLICATION (g)

3–6 mos 1–2 yrs

3–5 yrs 6–10 yrs

17.5

28

42

43

70

14.5

21.0

42

42

58

84

17.5

24.5

31.5

42

70

98

126

10.5

17.5

24.5

31.5

42

70

98

126

10.5

24.5

31.5

38.5

42

98

126

154

Topical Immunomodulatory Drugs

TABLE Estimating the Necessary Amount of Topical Corticosteroid for Children 45.8

CHAPTER 45

Topical Corticosteroids

527

• BOX 45.8 Sample Patient Instructions Handout Topical Corticosteroids MEDICATION: ______________________ DIRECTIONS: __________________________________ • This information summary is applicable to most topical corticosteroid preparations. • There is a large list of potential adverse effects from topical corticosteroids. Although patients’ awareness of these adverse effects is important, overconcern and overattention to these possible adverse effects is potentially disruptive and best avoided.

Contraindications • A bsolute contraindications to the use of a topical corticosteroid include known hypersensitivity (allergy) to the topical corticosteroid or a component of the vehicle. • Other possible contraindications include ulceration, scabies infestation, and bacterial, viral, mycobacterial, or fungal infection.

Adverse Effects Minor Effects from Short-Term Therapy (2–3 Weeks or Less) • I n the absence of any of the previously mentioned contraindications, topical corticosteroid therapy is rarely associated with serious adverse effects. • The most common adverse effects include mild irritation such as redness, burning, stinging or itching

Potential Effects From Long-Term Therapy • I mportant adverse effects from long-term therapy include skin atrophy (thinning) demonstrated by shiny, wrinkled, easily bruised skin, pigment changes, prominent small blood vessels, and ulceration.

toward allowing less frequent office visits, which typically means less opportunity for careful follow-up. More emphasis must be placed on educating the patient (or parent) at the first visit. From our experience, most patients cannot remember more than two or three instructions from a given visit; therefore, handouts on TCS are helpful. Box 45.8 lists a sample patient instructions handout.

Acknowledgment The authors would like to thank Michael R. Warner for his contribution to previous editions of this chapter.

Bibliography: Important Reviews and Chapters General Overviews Ahluwalia A. Topical glucocorticoids and the skin-mechanisms of action: an update. Mediators Inflamm. 1998;7(3):183–193. Chaffman MO. Topical corticosteroids: a review of properties and principles in therapeutic use. Nurse Pract Forum. 1999;10(2):95–105. Katz M, Gans EH. Topical corticosteroids, structure-activity and the glucocorticoid receptor: discovery and development – a process of ‘planned serendipity’. J Pharm Sci. 2008;97(8):2936–2937. Hajar T, Leshem YA, Hanifin JM, et  al. A systematic review of topical corticosteroid withdrawal (“steroid addiction”) in patients with atopic dermatitis and other dermatoses. J Am Acad Dermatol. 2015;72(3):541–549.e2. Li AW, Yin ES, Antaya RJ. Topical corticosteroid phobia in atopic dermatitis: a systematic review. JAMA Dermatol. 2017;153(10):1036–1042. Mehta AB, Nadkarni NJ, Patil SP, Godse KV, Gautam M, Agarwal S. Topical corticosteroids in dermatology. Indian J Dermatol Venereol Leprol. 2016;82(4):371–378.

• Long-term therapy with certain topical steroids (particular with use over large portions of your body) can lead to absorption into the blood system and can cause weight gain and fluid retention, blood pressure elevation, mood alterations, significant fever or chills, excessive thirst and urinary frequency or volume, or severe or persistent bone, joint, or muscle pain. • Long-term therapy can cause worsening of scabies, fungal, and yeast infections; extension of herpetic ulcers; increased susceptibility to fungal and bacterial infections; inflammation of hair follicles or sweat ducts; exacerbation of acne or rosacea; and glaucoma. • Local adverse effects generally occur at the site of application and are not common.

Special Circumstances • Usage in pregnancy should be restricted to times when the potential benefits justify possible risk to the fetus and with complete agreement from your physicians. • Use with caution when breastfeeding. Avoid application to the breast or nipple. It is not known if topical corticosteroids are distributed into the breast milk.

Summary • The vast majority of patients receiving short- or long-term topical corticosteroids do not experience important or serious adverse effects; however, early reporting to your physician of the more serious adverse effects listed earlier is important. • Apply the topical corticosteroid according to directions from your physician. • Incorrect usage of topical corticosteroids can greatly increase the risk of local and systemic adverse effects. • Do not share your product with other people.

Adverse Effects – Overviews Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol. 2006;54(1):1–15.

References* 3. Camisa C. Corticosteroids. In: Camisa C, ed. Psoriasis. 2nd ed. Boston: Blackwell Scientific; 2004:139–157. 19. Schäcke H, Berger M, Rehwinkel H, Asadullah K. Selective glucocorticoid receptor agonists (SEGRAs): novel ligands with an improved therapeutic index. Mol Cell Endocrinol. 2007;275(1–2):109–117. 52. Bleehan SS, Chu AC, Hamann I, Holden C, Hunter JA, Marks R. Fluticasone propionate 0.05% cream in the treatment of atopic eczema: a multicentre study comparing once-daily treatment and once-daily vehicle cream application versus twice-daily treatment. Br J Dermatol. 1995;133(4):592–597. 54. Hoffman LK, Kircik L. Efficacy and safety of desoximetasone 0.25% spray in adult atopic dermatitis subjects: pilot study. J Drugs Dermatol. 2017;16(9):919–922. 103. Gold LS, Lebwohl MG, Sugarman JL, et al. Safety and efficacy of a fixed combination of halobetasol and tazarotene in the treatment of moderate-tosevere plaque psoriasis: results of 2 phase 3 randomized controlled trials. J Am Acad Dermatol. 2018;79(2):287–293. 112. Gupta AK, Versteeg SG. Topical treatment of facial seborrheic dermatitis: a systematic review. Am J Clin Dermatol. 2017;18(2):193–213. 114. Brun J, Chiaverini C, Bessis D, et  al. [Wells syndrome in children and atopy: restrospective study of 11 cases and review of the literature]. Ann Dermatol Venereol. 2015;142(5):320–323. 127. Altenburg A, El-Haj N, Micheli C, Puttkammer M, Abdel-Naser MB, Zouboulis CC. The treatment of chronic recurrent oral aphthous ulcers. Dtsch Arztebl Int. 2014;111(40):665–673. 134. Fernández-de-Misa R, Hernández-Machín B, Servitje O, et  al. First-line treatment in lymphomatoid papulosis: a retrospective multicenter study. Clin Exp Dermatol. 2018;43(2):137–143.

*Only a selection of references are printed here. All other references in the reference list are available online at www.expert consult.com.

Web References Pharmacology 1. Stoughton RB. Vasoconstriction activity and percutaneous absorption of glucocorticosteroids. Arch Dermatol. 1969;99(6):753–756. 2. Cornell RC, Stoughton RB. Correlation of the vasoconstriction assay and clinical activity in psoriasis. Arch Dermatol. 1985;121(1):63–67. 3. Camisa C. Corticosteroids. In: Camisa C, ed. Psoriasis. 2nd ed. Boston: Blackwell Scientific; 2004:139–157. 4. Ponec M. Glucocorticoids and cultured human skin cells: specific intracellular binding and structure-activity relationships. Br J Dermatol. 1982;107(suppl 23):24–29. 5. Ponec M, Kenpenaar J, Shroot B, Caron JC. Glucocorticoids: binding affinity and lipophilicity. J Pharm Sci. 1986;75(10):973–975. 6. Bikowski J, Pillai R, Shroot B. The position not the presence of the halogen in corticosteroids influences potency and side effects. J Drugs Dermatol. 2006;5(2):125–130. 7. Phillips GH. Locally active corticosteroids: structure-activity relationships. In: Wilson L, Marks R, eds. Mechanisms of Topical Corticosteroid Activity. Edinburgh: Churchill Livingstone; 1976:1. 8. Kamm A. The pharmacologic profile of clobetasol propionate: a new high potency steroid. In: Clobetasol: An Investigator’s Report. Philadelphia: Glaxo Monograph; 1986:10–18. 9. Yohn JJ, Weston WL. Topical glucocorticosteroids. Curr Probl Dermatol. 1990;2:38–63. 10. Stoughton RB, Cornell RC. Topical steroids in dermatology. In: Christophers E, Schopf E, Kligman AM, et al., eds. Topical Corticosteroid Therapy: A Novel Approach to Safer Drugs. New York: Raven Press; 1988:1–12. 11. Vickers CF. Existence of a reservoir in the stratum corneum. Arch Dermatol. 1963;88:20–23. 12. Purdon CH, Haigh JM, Surber C, Smith EW. Foam drug delivery in dermatology: beyond the scalp. Am J Drug Deliv. 2003;1:71–75. 13. Clarys P, Gabard B, Barel AO. A qualitative estimate of the influence of halcinonide concentration and urea on the reservoir formation in the stratum corneum. Skin Pharmacol Appl Skin Physiol. 1999;12(1–2):85–89. Mechanisms of Action—General Concepts 14. Catt KJ, Dufau ML. Hormone action: control of target cell function by peptide, thyroid and steroid hormones. In: Felig P, Baxter JD, Broadus AE, et al., eds. Endocrinology and Metabolism. New York: McGraw-Hill; 1981:61–105. 15. Thompson EB. The structure of the human glucocorticoid receptor and its gene. J Steroid Biochem. 1987;27(1–3):105– 108. 16. Lan NC, Karin M, Nguyen T, et  al. Mechanisms of glucocorticoid hormone action. J Steroid Biochem. 1984;20(1): 77–88. 17. Spindler SR, Mellon SH, Baxter JD. Growth hormone gene transcription is regulated by thyroid and glucocorticoid hormones in cultured rat pituitary tumor cells. J Biol Chem. 1982;257(19):11627–11632. 18. Evans RM, Birnberg NC, Rosenfeld MG. Glucocorticoid and thyroid hormones transcriptionally regulate growth hormone gene expression. Proc Natl Acad Sci U S A. 1982;79(24):7659– 7663. 19. Schäcke H, Berger M, Rehwinkel H, Asadullah K. Selective glucocorticoid receptor agonists (SEGRAs): novel ligands with an improved therapeutic index. Mol Cell Endocrinol. 2007;275(1– 2):109–117.

Mechanisms of Action—Anti-inflammatory Effects 20. MacGregor RR. Inhibition of granulocyte adherence: potential mechanism of action of anti-inflammatory drugs. Clin Res. 1974;22:423A. 21. Dale DC, Rauci AS, Wolff SM. Alternate-day prednisone. Leukocyte kinetics and susceptibility to infections. N Engl J Med. 1974;291(22):1154–1158. 22. Dale DC, Fauci AS, Guerry DIV, Wolff SM. Comparison of agents producing a neutrophilic leukocytosis in man. Hydrocortisone, prednisone, endotoxin, and etiocholanolone. J Clin Invest. 1975;56(4):808–813. 23. Rebuck JW, Mellinger RC. Interruption by topical cortisone of leukocyte cycles in acute inflammation in man. Ann N Y Acad Sci. 1953;56(4):715–732. 24. Balow JE, Rosenthal AS. Glucocorticoid suppression of macrophage inhibitory factor. J Exp Med. 1973;137(4):1031–1041. 25. Weston WL, Claman HN, Krueger CG. Site of action of cortisol in cellular immunity. J Immunol. 1973;110(3):880–883. 26. Rinehart JJ, Balcerzak SP, Sagone AL, LoBuglio AF. Effects of corticosteroids on human monocyte function. J Clin Invest. 1974;54(6):1337–1343. 27. Hattori T, Hirata F, Hoffman T, Hizuta A, Herberman RB. Inhibition of human natural killer (NK) activity and antibodydependent cellular cytotoxicity (ADCC) by lipomodulin, a phospholipase inhibitory protein. J Immunol. 1983;131(2):662–665. 28. Hoffman T, Hirata F, Bougnouz P, et al. Phospholipid methylation and phospholipase A2 activation in cytotoxicity by human natural killer cells. Proc Natl Acad Sci U S A. 1981;78(6):3839– 3843. 29. Hellewell PG, Williams TJ. An anti-inflammatory steroid inhibits tissue sensitization by IgE in  vivo. Br J Pharmacol. 1989;96(1):5–7. 30. Altura BM. Role of glucocorticoids in local regulation of blood flow. Am J Physiol. 1966;211(6):1393–1397. 31. Guyre PM, Bodwell JE, Hollbrook NJ, et al. Glucocorticoids and the immune system: activation of glucocorticoid-receptor complexes in thymus cells; modulation of Fc receptors of phagocytic cells. In: Lee HJ, Walker CA, eds. Progress in Research and Clinical Applications of Corticosteroids. Philadelphia: Heyden; 1981:14–27. 32. DiRosa M, Flower RJ, Hirata F, Parente L, Russo-Marie F. Anti-phospholipase proteins. Prostaglandins. 1984;28(4):441– 442. 33. Ramey ER, Goldstein MS. The adrenal cortex and the sympathetic nervous system. Physiol Rev. 1957;37(2):155–195. 34. Fritz I, Levine R. Action of adrenal cortical steroids and norepinephrine on vascular responses of stress in adrenalectomized rats. Am J Physiol. 1951;165(2):456–465. 35. Besse JC, Bass AD. Potentiation by hydrocortisone of responses to catecholamines in vascular smooth muscle. J Pharmacol Exp Ther. 1966;154(2):224–238. 36. Kalsner S. Steroid potentiation of responses to sympathomimetic amines in aortic strips. Br J Pharmacol. 1969;36(3): 582–593. Mechanisms of Action—Antiproliferative and Atrophogenic Effects 37. Marks R, Williams K. The action of topical steroids on the epidermal cell cycle. In: Wilson L, Marks R, eds. Mechanisms of Topical Corticosteroid Activity. Edinburgh: Churchill Livingstone; 1976:39. 38. Fisher LB, Maibach HI. The effect of corticosteroids on human epidermal mitotic activity. Arch Dermatol. 1971;103(1):39–44. 39. Lehman P, Zheng P, Lavker RM, Kligman AM. Corticosteroid atrophy in human skin. A study by light, scanning, and transmission electron microscopy. J Invest Dermatol. 1983;81(2):169–176.

527.e1

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163. Eichenfield LF, Basu S, Calvarese B, Trancik RJ. Effect of desonide hydrogel 0.05% on the hypothalamic-pituitary-adrenal axis in pediatric subjects with moderate to severe atopic dermatitis. Pediatr Dermatol. 2007;24(3):289–295. 164. Hebert AA, Friedlander SF, Allen DB. Topical fluticasone propionate lotion does not cause HPA axis suppression. J Pediatr. 2006;149(3):378–382. 165. Chi CC, Kirtschig G, Aberer W, et  al. Evidence-based (S3) guideline on topical corticosteroids in pregnancy. Br J Dermatol. 2011;165(5):943–952. 166. Chi CC, Mayon-White RT, Wojnarowska FT. Safety of topical corticosteroids in pregnancy: a population-based cohort study. J Invest Dermatol. 2011;131(4):884–891. Local Adverse Effects—General Issues 167. Akers WA. Risks of unoccluded topical steroids in clinical trials. Arch Dermatol. 1980;116(7):786–788. Atrophy Effects 168. Kligman AM. Adverse effects of topical corticosteroids. In: Christophers E, Schopf E, Kligman AM, et al., eds. Topical Corticosteroid Therapy: A Novel Approach to Safer Drugs. New York: Raven Press; 1988:181–187. 169. Kirby JD, Munro DD. Steroid-induced atrophy in an animal and human model. Br J Dermatol. 1976;94(suppl 12): 111–119. 170. Katz HI, Prawer SE, Mooney JJ, Samson CR. Preatrophy: covert sign of thinned skin. J Am Acad Dermatol. 1989;20(5Pt1): 731–735. 171. Feldman RJ, Maibach HI. Regional variation in percutaneous penetration of 14C cortisol in man. J Invest Dermatol. 1967;48(2):181–183. 172. Johns AM, Bower BD. Wasting of the napkin area after repeated use of fluorinated steroid ointment. Br Med J. 1970;1(5692):347–348. Addiction/Rebound Syndrome and Perioral Dermatitis 173. O’Donoghue MN. Perioral dermatitis. In: Arndt KA, Leboit PE, Robinson JK, et al., eds. Cutaneous Medicine and Surgery. Philadelphia: WB Saunders; 1996:497–502. 174. Rapaport MJ, Rapaport V. Eyelid dermatitis to red face syndrome to cure: Clinical experience in 100 cases. J Am Acad Dermatol. 1999;41(3Pt1):435–442. 175. Fulton JE, Kligman AM. Aggravation of acne vulgaris by topical application of corticosteroids under occlusion. Cutis. 1968;4:1106–1109. 176. Leyden JJ, Thew M, Kligman AM. Steroid rosacea. Arch Dermatol. 1974;110(4):619–622. 177. MacMillan AL. Unusual features of scabies associated with topical fluorinated steroids. Br J Dermatol. 1972;87(5):496–497. 178. Ive FA, Marks R. Tinea incognito. Br Med J. 1968;3(5611):149– 152. 179. Harlan SL. Streroid acne and rebound phenomenon. J Drugs Dermatol. 2008;7(6):547–550. Ocular Effects 180. Wilson 2nd FM. Adverse external ocular effects of topical ophthalmic medications. Surv Ophthalmol. 1979;24(2):57–88. 181. Haeck IM, Rouwen TJ, Timmer-de Mik L, de Bruin-Weller MS, Bruijnzeel-Koomen CA. Topical corticosteroids in atopic dermatitis and the risk of glaucoma and cataracts. J Am Acad Dermatol. 2011;64(2):275–281. 182. Aggarwa RK, Potamitis T, Chong NH, Guarro M, Shah P, Kheterpal S. Extensive visual loss with topical facial steroids. Eye (Lond). 1993;7(Pt5):664–666. 183. thoe Schwartzenberg GW, Buys YM. Glaucoma secondary to topical use of steroid cream. Can J Ophthalmol. 1999;34(4):222– 225.

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References

Allergic Contact Dermatitis To Topical Corticosteroid Molecule 184. Pratt MD, Belsito DV, DeLeo VA, et  al. North American Contact Dermatitis Group patch-test results, 2001-2002 study period. Dermatitis. 2004;15(4):176–183. 185. Isaksson M, Bruze M. Contact allergen of the year: corticosteroids. Dermatitis. 2005;16(1):3–5. 186. Hayakawa R, Matsunaga K, Suzuki M, et  al. Allergic contact dermatitis due to budesonide. Contact Dermatitis. 1991;24(2):136–137. 187. Stingeni L, Caraffin S, Assalve D, Lapomarda V, Lisi P. EMlike contact dermatitis from budesonide. Contact Dermatitis. 1996;34(2):154–155. 188. Miranda-Romero A, Sánchez-Sambucety P, Bajo C, Martinez M, Garcia-Munõz M. Genital oedema from contact allergy to prednicarbate. Contact Dermatitis. 1998;38(4):228–229. 189. Isaksson M. Corticosteroids. Dermatol Ther. 2004;17(4):314– 320. 190. Jacob SE, Steele T. Corticosteroid classes: a quick reference guide including patch test substances and cross-reactivity. J Am Acad Dermatol. 2006;54(4):723–727. 191. Scheuer E, Warshaw E. Allergy to corticosteroids: update and review of epidemiology, clinical characteristics, and structural cross-reactivity. Am J Contact Dermat. 2003;14(4):179–187. 192. Bircher AJ, Levy F, Langauer S, Lepoittevin JP. Contact allergy to topical corticosteroids and systemic contact dermatitis from prednisolone with tolerance of triamcinolone. Acta Derm Venereol. 1995;75(6):490–493. Tachyphylaxis 193. du Vivier A, Stoughton RB. Tachyphylaxis to the action of topically applied corticosteroids. Arch Dermatol. 1975;111(5): 581–583. 194. du Vivier A. Tachyphylaxis to topically applied steroids. Arch Dermatol. 1976;112(9):1245–1248. 195. du Vivier A, Stoughton RB. Acute tolerance to effects of topical glucocorticosteroids. Br J Dermatol. 1976;94(suppl 12):25–32. 196. du Vivier A, Phillips H, Hehir M. Applications of glucocorticosteroids. Arch Dermatol. 1982;118(5):305–308. 197. Singh S, Gupta A, Pandey SS, Singh G. Tachyphylaxis to histamine-induced wheal suppression by topical 0.05% clobetasol propionate in normal versus croton oil-induced dermatitic skin. Dermatology. 1996;193(2):121–123. 198. Miller JJ, Roling D, Margolis D, Guzzo C. Failure to demonstrate therapeutic tachyphylaxis to topically applied steroids in patients with psoriasis. J Am Acad Dermatol. 1999;41(4): 546–549. 199. Feldman SR. Tachyphylaxis to topical corticosteroids: the more you use them, the less they work? Clin Dermatol. 2006;24(3):229–230.

Other Local Adverse Effects 200. Marlière V, Roul S, Labrèze C, Taïeb A. Crusted (Norwegian) scabies induced by use of topical corticosteroids and treated successfully with ivermectin. J Pediatr. 1999;135(1):122–124. 201. Pérez E, Barnadas MA, García-Patos V, et al. Kaposi’s sarcoma in a patient with erythroblastopenia and thymoma: reactivation after topical corticosteroids. Dermatology. 1998;197(3):264–267. Adverse Effects Due To the Topical Corticosteroid Vehicle 202. Warner MR, Taylor JS, Leow YH. Agents causing contact urticaria. Clin Dermatol. 1997;15(4):623–635. 203. Coloe J, Zirwas MJ. Allergens in corticosteroid vehicles. Dermatitis. 2008;19(1):38–42. Therapeutic Guidelines 204. Stoughton RB. Are generic formulations equivalent to trade name topical glucocorticoids? Arch Dermatol. 1987;123(10):1312– 1314. 205. Olsen EA. A double blind controlled comparison of generic and trade name topical steroids using the vasoconstriction assay. Arch Dermatol. 1991;127(2):197–201. 206. Jackson DB, Thompson C, McCormack JR, Guin JD. Bioequivalence (bioavailability) of generic topical corticosteroids. J Am Acad Dermatol. 1989;20(5Pt1):791–796. 207. Stoughton RB, Wullich K. The same glucocorticoid in brandname products. Arch Dermatol. 1989;125(11):1509–1511. 208. Green C, Colquitt JL, Kirby J, Davidson P, Payne E. Clinical and cost-effectiveness of once-daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systemic review and economic evaluation. Health Technol Assess. 2004;8(47). iii,iv,1–120. 209. Green C, Colquitt JL, Kirby J, Davidson P. Topical corticosteroids for atopic eczema: clinical and cost effectiveness of once-daily vs. more frequent use. Br J Dermatol. 2005;152(1):130–141. 210. Epstein E. Is tacrolimus more cost-effective than high potency corticosteroids are in the treatment of atopic dermatitis? J Am Acad Dermatol. 2004;51(4):670–671. 211. Ellis CN, Drake LA, Prendergast MM, et al. Cost-effectiveness analysis of tacrolimus ointment versus high-potency topical corticosteroids in adults with moderate to severe atopic dermatitis. J Am Acad Dermatol. 2003;48(4):553–563. 212. Long CC, Finlay AY. The fingertip unit—a new practical measure. Clin Exp Dermatol. 1991;16(6):444–447. 213. Timmins P, Gray EA. Degradation of hydrocortisone in a zinc oxide lotion. J Clin Hosp Pharm. 1983;8(1):79–85. 214. Krochmal L, Wang JC, Patel B, Rodgers J. Topical corticosteroid compounding: effects on physiochemical stability and skin penetration rate. J Am Acad Dermatol. 1989;21(5Pt1):979–984.

46 Topical Retinoids NAVEED SAMI AND SALMA DE LA FELD

QUESTIONS Q46.1 Concerning topical retinoids in this chapter, what are (1) the three naturally occurring retinoids, (2) the three synthetic retinoids, and (3) the metabolic differences likely because of this distinction? (Pg. 529, Table 46.1) Q46.2 Which of the topical retinoids have a traditional pregnancy rating (1) category D, and (2) category X? (Pg. 529, Table 46.3) Q46.3 Concerning the correlation of increased retinoid serum levels and teratogenicity, what are several of the variables that increase serum levels of topical retinoids? (Pg. 529)

Q46.7 In general, what are the concise effects of RAR and RXR on (1) cellular differentiation, and (2) apoptosis? (Pg. 536) Q46.8 Which topical retinoids have a US Food and Drug Administration-approved indication for (1) psoriasis, (2) cutaneous T-cell lymphoma, and (3) acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma? (Pg. 536, Table 46.7) Q46.9 What are several of the mechanisms by which patients with acne vulgaris benefit from various topical retinoids? (Pg. 536)

Q46.4 What are the major steps of normal vitamin A physiology from absorption through gene transcription? (Pg. 532, Fig. 46.2)

Q46.10 What are the two primary negative effects of ultraviolet radiation on users of topical retinoids, and how do various topical retinoids differ regarding these negative effects? (Pgs. 537, 538)

Q46.5 Which topical retinoids bind to (1) retinoic acid receptor (RAR), (2) retinoid X receptor (RXR), and (3) both RAR and RXR? (Pg. 532, Table 46.5)

Q46.11 Concerning topical retinoids used for treatment of photoaging, what are (1) the mechanisms of action leading to improvement, and (2) the histologic changes noted? (Pg. 537)

Q46.6 Regarding the prodrug tazarotene, (1) what is the active drug form, and (2) what are several of the relatively unique effects at the gene transcription level? (Pg. 534)

Q46.12 What are several product categories which increase the risk of irritancy when used concomitantly with topical retinoids? (Pg. 539)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R 5-FU 5-Fluorouracil AE Adverse effects (events) AP-1 Activator protein-1 ARAT Acyl CoA:retinol acyltransferase CCR4 Chemokine receptor 4 CRABP Cytosolic retinoic acid-binding protein CRBP Cytosolic retinol-binding protein CTCL Cutaneous T-cell lymphoma EGF Epidermal growth factor KS Kaposi sarcoma LRAT Lecithin:retinol acyltransferase MMP Matrix metalloproteinase MRP-8 Migration inhibitory factor-related protein-8 NFAT Nuclear factor of activated T cells NFκB Nuclear factor κ B

528

PAMP Pathogen-associated molecular pattern PARP Poly (ADP-ribose) polymerase PPAR Peroxisome proliferator-activated receptor RAR (Nuclear) retinoic acid receptor RARE Retinoic acid response elements RBP Retinoid-binding protein RXR Retinoid X receptor Tgase I Transglutaminase I TIG Tazarotene-inducible gene TIMP Tissue inhibitor of metalloproteinase TLR Toll-like receptor TRP-1 Tyrosine-related protein-1 UVR Ultraviolet radiation VEGF Vascular endothelial growth factor

CHAPTER 46

Introduction Topical forms of vitamin A (retinoids) have been widely used in the United States since 1971. The first retinoid to be used topically, all-trans retinoic acid, was developed by Dr. Albert Kligman at the University of Pennsylvania.1 This product was subsequently brought to market in the 1970s for the treatment of acne vulgaris by Ortho Pharmaceuticals as Retin-A. Approximately 10 years later, Kligman and colleagues noted that middle-aged women with acne were reluctant to stop the Retin-A therapy, even when their acne was under good control, because they perceived an improvement in fine lines and general skin appearance. This effect on photoaging was first published in 1986.2 Numerous clinical and basic science studies were subsequently published to more clearly define the efficacy of Retin-A in photoaging. Tretinoin is still prescribed for both acne vulgaris and photoaging. It is available in several formulations that incorporate unique vehicles and delivery systems. In addition to tretinoin, several other topical retinoids have been developed more recently for the treatment of acne vulgaris. Additional topical retinoids have been developed and approved for the treatment of skin diseases, including psoriasis, Kaposi sarcoma, and cutaneous T-cell lymphoma (CTCL) (Table 46.1).3–5

Topical Retinoids

529

has the binding proteins and enzymatic machinery in place to properly metabolize these retinoids. In comparison, significant structural differences are evident for adapalene, tazarotene, and bexarotene, which are not naturally occurring retinoids, making metabolic pathways more challenging to predict.7,8 The structure of the different retinoids is important because it determines how they are transported in the bloodstream and within cells. Affinity to binding proteins, both cytoplasmic and nuclear, is critical for retinoid effects on gene transcription and resultant biologic activity.

Mechanism of Action Q46.2 The topical retinoid drug mechanisms (Table 46.2) and additional important pharmacologic concepts are summarized in Table 46.3. This allows easy comparison between the natural and synthetic topical retinoids discussed in this chapter. The following paragraphs concerning each specific drug discuss further details concerning: (1) serum and cellular binding proteins; (2) nuclear receptors/transcription factors; (3) other details of each drug’s mechanism, including gene regulation; and (4) absorption, metabolism, and excretion.

Teratogenicity

Pharmacology Structure The structures of several of the retinoids discussed in this chapter are shown in Fig. 46.1. Q46.1 Note that tretinoin represents an oxidized form of all-trans retinol. It is endogenously synthesized in the skin from all-trans retinol after delivery of this compound to basal keratinocytes via the bloodstream.6 Alitretinoin (9-cis retinoic acid) is also a naturally occurring endogenous retinoid.5 Because all-trans retinoic acid (tretinoin), all-trans retinol, and alitretinoin are naturally occurring retinoids, the human body

Many tissues require vitamin A for normal growth and differentiation. Q46.3 Excessive quantities adversely affect the developing embryo and fetus of a number of animal species.9,10 Thus, although topical absorption of retinoids is generally slight, there is a potential concern for systemic effects when large surface areas are treated. For example, patients with psoriasis potentially have large surface areas involved with disruption of the epidermal barrier; therefore, the rate of retinoid absorption is likely to be significantly increased. A pregnancy test is recommended before the use of tazarotene and bexarotene in women of childbearing potential, and appropriate birth control measures should be in place

TABLE Topical Retinoids 46.1

Generic Name

Trade Name

Date Released

Formulations Available

Natural or Synthetic

All-trans retinoic acid

Retin-A, Altinac

1971

Natural

Renova Avita

1996 1996

Retin-A Micro

1997

0.01%, 0.025%, 0.038%, 0.05%, 0.1% cream 0.01%, 0.025% gel, 0.05% gel 0.05% solution, 0.05% lotion 0.02%, 0.05% cream 0.025% cream 0.025% gel 0.1% cream 0.04%, 0.06%, 0.08%, 0.1% gel

Tazarotene

Tazorac, Avage

1997

0.05%, 0.1% cream 0.05%, 0.1% gel 0.1% foam

Synthetic

Adapalene

Differin

1996

0.1% cream 0.1% gel, 0.3% gel 0.1% solution

Synthetic

Alitretinoin

Panretin

1999

0.1% gel

Natural

Bexarotene

Targretin

2000

1% gel

Synthetic

530

PA RT I X

Topical Immunomodulatory Drugs

H3C

CH3

CH3

CH3

H3C

CH3

H3C

CH3

CH2

H3C

CH3 COOH

Alitretinoin

H3C

COOH

Bexarotene

CH3

CH3

CH3

COOH

CH3 Tretinoin

COOH

O H3NO

N

COC2H5

CH3

H3C CH2 H2 H2 C C S

Tazarotene

Adapalene

• Fig. 46.1

Topical retinoids.

TABLE 46.2 Topical Retinoid Drug Mechanisms

Retinoid

Mechanism of Action

Resultant Therapeutic Effects

Resultant Adverse Effects

All-trans retinol Gene transcription after conversion to all-trans retinoic acid

Comedolysis, epidermal thickening, dermal regeneration, pigment lightening

Irritation, erythema, desquamation

All-trans retinoic acid

Gene transcription affects growth and differentiation of cells in the skin Normalizes follicular epithelial differentiation and keratinization

Comedolysis Palliative effects on fine wrinkling, mottled hyperpigmentation, and tactile roughness of facial skin

Irritation, erythema, desquamation

Adapalene

Normalizes the differentiation of follicular epithelial cells leading to decreased microcomedone formation Suppression of PMN chemotaxis Downregulation of 5- and 15-lipoxygenase, AP-1 transcription factor, and Toll-like receptors type II Increase in IL-1, IL-6, IL-8, TNF-α production

Comedolysis

Irritation, erythema, desquamation, pruritus, burning

Tazarotene

Blocks induction of ornithine decarboxylase activity with decreased cell proliferation and hyperplasia Suppresses MRP-8 (a marker of inflammation in psoriasis), involucrin, keratinocytes glutaminase, elafin, keratin 6 &16 Also inhibits cornified envelope formation and corneocyte accumulation in Rhino mouse skin Inhibits cross-linked cornified envelope formation Increases filaggrin

Normalization of differentiation and proliferation of the epidermal keratinocytes in psoriasis Also comedolysis in acne

Irritation, erythema, desquamation, pruritus, burning Worsening of psoriasis Photosensitivity Dry skin, fissuring, bleeding Also teratogenic precautions

Continued

CHAPTER 46

Topical Retinoids

531

TABLE Topical Retinoid Drug Mechanisms—cont’d 46.2

Retinoid

Mechanism of Action

Resultant Therapeutic Effects

Resultant Adverse Effects

Alitretinoin

Binds and activates RAR and RXR subtypes that modulate the expression of genes that control cellular differentiation and proliferation

Inhibits the growth of Kaposi sarcoma cells in vitro Increased cellular differentiation and decreased proliferation

Irritant contact dermatitis, erythema, scaling, pruritus Teratogenic precautions

Bexarotene

Modulation of RXR receptors Increased apoptosis through reduction of antiapoptotic protein (survivin), and via activation of caspase-3

aInduces

Irritant contact dermatitis, erythema, scaling, pruritus Teratogenic precautions

tumor regression and inhibits growth of tumor cells lines of hematopoietic and keratinocytes Increased cellular differentiation and decreased cellular growth

aPrimarily

data from oral bexarotene. Similar data are not available for topical bexarotene. AP-1, Activating protein-1; IL, interleukin; MRP-8, migration inhibitory factor-related protein; PMN, polymorphonuclear leukocytes; RAR, retinoic acid receptor; RXR, retinoid X receptor; TNF, tumor necrosis factor.

TABLE Key Pharmacology Concepts—Topical Retinoids 46.3

All-Trans Retinol

All-Trans Retinoic Acid

Systemic absorption

N/A

Onset of action

Drug

Adapalene

Tazarotene

Alitretinoin

Bexarotene

1%–2% in normal skin; up to 31% in dermatitic skin

Trace amounts

Up to 5% topically applied to normal skin; up to 15% in psoriatic skin

Not measurable

Trace amounts (30%) or with a lower pH than these thresholds would be recommended only for medical use supervised by a physician. Q52.8 Based on current knowledge, it is advisable for patients to wear an adequate sunscreen when using AHA.

Herpes Simplex Infections Very rarely, a herpes infection can be triggered with a glycolic acid peel because of chemical and/or inflammatory trauma. Thus, prophylactic acyclovir, or similar oral antiviral medications, can be used to minimize postoperative herpetic infections in patients who are prone to such outbreaks.50

Summary With their diverse properties and adaptability to many clinical scenarios, it is no wonder AHA are one of the most popular classes of dermatological agents. Evidence supports the efficacy of AHA for the treatment of photodamaged skin, hyperpigmentation, acne and rosacea, and as a keratolytic for treatment of xerosis, icthyosis and psoriasis. Irritation and photosensitivity are the main AE; however, historical concerns about increased risk of photocarcinogenesis seem to be unfounded. The clinician needs to use sound medical judgment when determining what AHA concentration, pH level, and application schedule is appropriate for individual patients. When prescribing an AHA treatment, physicians should always recommend the use of broad-spectrum sunscreens to combat the risk of increased photosensitivity.

CHAPTER 52

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References* 1. Kornhauser A, Coelho SG, Hearing VJ. Applications of hydroxyl acids: classifications, mechanisms, and photoactivity. Clin Cosmet Investig Dermatol. 2010;3:135–142. 7. Ditre CM, Griffin TD, Murphy GF, et al. Effects of α-hydroxy acids on photoaged skin: a pilot clinical, histologic, and ultrastructural study. J Am Acad Dermatol. 1996;34(2Pt1):187–195.

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13. Edison BL, Green BA, Wildnauer RH, Sigler ML. A polyhydroxy acid skin care regimen provides antiaging effects comparable to an alpha-hydroxyacid regimen. Cutis. 2004;73(suppl 2):14–17. 14. Leyden J, Lavker RM, Groove G, et al. α hydroxy acids are more than moisturizers. J Ger Dermatol. 1995;3(suppl 3):33A–37A. 22. Sarkar R, Kaur C, Bhalla M, Kanwar AJ. The combination of glycolic acid peels with a topical regimen in the treatment of melasma in dark-skinned patients: a comparative study. Dermatol Surg. 2002;28(9):828–832. 24. Van Scott EJ, Yu RJ. α hydroxy acids. Therapeutic potentials. Can J Dermatol. 1989;1:108–112. 29. Dréno B, Fischer TC, Perosino E, et al. Expert opinion: efficacy of superficial chemical peels in active acne management–what can we learn from the literature today? Evidence-based recommendations. J Eur Acad Dermatol Venereol. 2011;25(6):695–704. 32. Berstein EF, Green B, Edison B, et al. Poly hydroxy acids: clinical uses for the next generation of hydroxy acids. Skin Aging. 2001;9:4–11. 40. Yu RJ, Van Scott EJ. Bioavailability of α-hydroxy acids in topical formulations. Cosmet Dermatol. 1996;9:954–962. 46. Kornhauser A, Wei R, Yamaguchi Y, et  al. The effects of topically applied glycolic acid and salicylic acid on ultraviolet radiation-induced erythema, DNA damage and sunburn cell formation in human skin. J Dermatol Sci. 2009;55(1):10–17.

*Only a selection of references are printed here. All other references in the reference list are available online at www.experteonsult.com.

Web References 1. Kornhauser A, Coelho SG, Hearing VJ. Applications of hydroxyl acids: classifications, mechanisms, and photoactivity. Clin Cosmet Investig Dermatol. 2010;3:135–142. 2. Van Scott EJ, Yu RJ. Control of keratinization with the α hydroxy acids and related compounds. Arch Dermatol. 1974;110: 586–590. 3. Wang X. A theory for the mechanism of action of the α-hydroxy acids applied to the skin. Med Hypotheses. 1999;53:380–382. 4. Usuki A, Ohasi A, Sato H. The inhibitory effect of glycolic acid and lactic acid on melanin synthesis in melanoma cells. Exp Dermatol. 2003;12(suppl 2):43–50. 5. Lanker RM, Kaidby K, Leyden J. Effects of topical ammonium lactate on cutaneous atrophy from a potent topical steroid. J Am Acad Dermatol. 1992;26:535–544. 6. Bernstein EF, Lee J, Brown DB, Yu R, Van Scott E. Glycolic acid treatment increases type I collagen mRNA and hyaluronic acid content of human skin. Dermatol Surg. 2001;27(5):429–433. 7. Ditre CM, Griffin TD, Murphy GF, et al. Effects of α-hydroxy acids on photoaged skin: a pilot clinical, histologic, and ultrastructural study. J Am Acad Dermatol. 1996;34(2Pt1):187–195. 8. Kim SJ, Won YH. The effect of glycolic acid on cultured human skin fibroblasts: cell proliferative effect and increased collagen synthesis. J Dermatol. 1998;25:85–89. 9. Okano Y, Abe Y, Masaki H, Santhanam U, Ichihashi M, Funasaka Y. Biological effects of glycolic acid on dermal matrix metabolism mediated by dermal fibroblasts and epidermal keratinocytres. Exp Dermatol. 2003;12(suppl 2):57–63. 10. Bernstein EF, Underhill CB, Lakkaakorpi J, et  al. Citric acid increases viable epidermal thickness and glycosaminoglycan content of sun-damaged skin. Dermatol Surg. 1997;23(8):689–694. 11. Perricone NV. An α hydroxy acid as an antioxidant. J Ger Dermatol. 1995;3(suppl 3):19A–25A. 12. Berardesca E, Distante F, Vignoli GP, Oresajo C, Green B. Alpha hydroxyacids modulate stratum corneum barrier function. Br J Dermatol. 1997;137(6):934–938. 13. Edison BL, Green BA, Wildnauer RH, Sigler ML. A polyhydroxy acid skin care regimen provides antiaging effects comparable to an alpha-hydroxyacid regimen. Cutis. 2004;73(suppl 2):14–17. 14. Leyden J, Lavker RM, Groove G, et al. α hydroxy acids are more than moisturizers. J Ger Dermatol. 1995;3(suppl 3):33A–37A. 15. Kempers S, Katz HI, Wildnauer R, Green B. An evaluation of the effect of an α hydroxy acid-blend skin cream in the cosmetic improvement of symptoms of moderate to severe xerosis, epidermolytic hyperkeratosis, and ichthyosis. Cutis. 1998;61(6):347–350. 16. Bernstein EF, Uitto J. Connective tissue alterations in photodamaged skin and the effects of α hydroxy acids. J Ger Dermatol. 1995;3(suppl 3):7A–18A. 17. Fartasch M, Teal J, Menon GK. Mode of action of glycolic acid on human stratum corneum: ultrastructural and functional evaluation of the epidermal barrier. Arch Dermatol Res. 1997;289(7):404–409. 18. Moon SE, Park SB, Ahn HT, Youn JI. The effect of glycolic acid on photoaged albino hairless mouse skin. Dermatol Surg. 1999;25:179–182. 19. Stiller MJ, Bartolone J, Stern R, et al. Topical 8% glycolic acid and 12% L-lactic acid creams for the treatment of photodamaged skin. A double blind vehicle-controlled clinical trial. Arch Dermatol. 1996;132(6):631–636. 20. Kligman AM. The compatibility of combinations of glycolic acid and tretinoin in acne and in photoaged skin. J Ger Dermatol. 1995;3(suppl A):25A–28A. 21. Yamamoto Y, Uede K, Yonei N, Kishioka A, Ohtani T, Furukawa F. Effects of α-hydroxy acids on the human skin of Japanese subjects: the rational for chemical peeling. J Dermatol. 2006;33(1):16–22.

22. Sarkar R, Kaur C, Bhalla M, Kanwar AJ. The combination of glycolic acid peels with a topical regimen in the treatment of melasma in dark-skinned patients: a comparative study. Dermatol Surg. 2002;28(9):828–832. 23. Dayal S, Sahu P, Dua R. Combination of glycolic acid peel and topical 20% azelaic acid cream in melasma patients: efficacy and improvement in quality of life. J Cosmet Dermatol. 2017;16(1):35–42. 24. Van Scott EJ, Yu RJ. α hydroxy acids. Therapeutic potentials. Can J Dermatol. 1989;1:108–112. 25. Briden ME, Cacatua LS, Patriots MA, et al. Treatment of acne with glycolic acid. J Ger Dermatol. 1996;4(SB):22B–27B. 26. Kim SJ, Baek JH, Koh JS, Bae MI, Lee SJ, Shin MK. The effect of physically applied alpha hydroxyl acids on the skin pore and comedone. Int J Cosmet Sci. 2015;37(5):519–525. 27. Kligman A. Result of a pilot study evaluating the compatibility of topical tretinoin in combination with glycolic acid. Cosmet Dermatol. 1993;6:28–32. 28. Elson ML. Differential effects of glycolic acid and tretinoin in acne vulgaris. Cosmet Dermatol. 1992;5:36–40. 29. Dréno B, Fischer TC, Perosino E, et al. Expert opinion: efficacy of superficial chemical peels in active acne management–what can we learn from the literature today? Evidence-based recommendations. J Eur Acad Dermatol Venereol. 2011;25(6):695–704. 30. Roberts WE. Chemical peeling in ethnic/dark skin. Dermatol Ther. 2004;17(2):196–205. 31. Briden ME, Rent-Pellerano MI. Treatment of rosacea with glycolic acid. J Ger Dermatol. 1996;4(SB):17B–21B. 32. Berstein EF, Green B, Edison B, et al. Poly hydroxy acids: clinical uses for the next generation of hydroxy acids. Skin Aging. 2001;9:4–11. 33. Draelos ZD, Green BA, Edison BL. An evaluation of a polyhydroxy acid skin care regimen in comgination with azelaic acid 15% gel in rosacea patients. J Cosmet Dermatol. 2006;5:23–29. 34. Akamine KL, Gustafson CJ, Yentzer BA, et al. A double-blind, randomized clinical trial of 20% alpha/poly hydroxy acid cream to reduce scaling of lesions associated with moderate, chronic plaque psoriasis. J Drugs Dermatol. 2013;12(8):855–859. 35. Kostarelos K, Teknetzis A, Lefaki I, Ioannides D, Minas A. Double-blind clinical study reveals synergistic action between alpha-hydroxy acid and betamethasone lotions towards topical treatment of scalp psoriasis. J Eur Acad Dermatol Venereol. 2000;14(1):5–9. 36. Green BA, Yu RJ, Van Scott EJ. Clinical and cosmeceutical uses of hydroxyacids. Clin Dermatol. 2009;27(5):495–501. 37. Callen JP, Bickers DR, Moy RL. Actinic keratoses. J Am Acad Dermatol. 1997;36(4):650–653. 38. Goldberg DJ. Case-based experience in the use of 5-fluorouracil cream 0.5% as monotherapy and in conjunction with glycolic acid peels for the treatment of actinic keratosis. J Cosmet Laser Ther. 2010;12(1):42–46. 39. Cook KK. Chemical peeling of non-facial skin using glycolic acid gel augmented with TCA and neutralized based on visual staging. Dermatol Surg. 2000;26:994–999. 40. Yu RJ, Van Scott EJ. Bioavailability of α-hydroxy acids in topical formulations. Cosmet Dermatol. 1996;9:954–962. 41. Smith WP. Comparative effectiveness of α-hydroxy acids on skin properties. Intl J Cosmet Sci. 1996;18:75–83. 42. US Food and Drug Administration. Cosmetics: Alpha Hydroxy Acids; 2018. Retrieved from https://www.fda.gov/cosmetics/ productsingredients/ingredients/ucm107940.htm#q4. Accessed January 14, 2019. 43. Scientific Literature Review. On Glycolic and Lactic Acids, Their Common Salts, and Their Simple Esters. Final Report. April 7, 1995. Washington, DC: Cosmetic Ingredient Review; 1995. 44. Dinardo JC. Studies show cumulative irritation potential based on pH. Cosmet Dermatol. 1996;9(suppl 5):12–13.

591.e1

591.e2

References

45. Tsai TF, Bowman HP, Jee SH, Maibach HI. Effects of glycolic acid on light-induced skin pigmentation in Asian and Caucasian subjects. J Am Acad Dermatol. 2000;43(2Pt1):238–243. 46. Kornhauser A, Wei R, Yamaguchi Y, et al. The effects of topically applied glycolic acid and salicylic acid on ultraviolet radiationinduced erythema, DNA damage and sunburn cell formation in human skin. J Dermatol Sci. 2009;55(1):10–17. 47. Bernstein EF, Brown DB, Schwartz MD, Kaidbey K, Ksenzenko SM. The polyhydroxy acid gluconolactone protects against ultraviolet radiation in an in  vitro model of cutaneous photoaging. Dermatol Surg. 2004;30(2Pt1):189–195. discussion 196.

48. Hong JT, Kim EJ, Ahn KS, et al. Inhibitory effect of glycolic acid on ultraviolet-induced skin tumorigenesis in SKH-1 hairless mice and its mechanism of action. Mol Carcinog. 2001;31(3):152–160. 49. National Toxicology Program. Photocarcinogenesis study of glycolic acid and salicylic acid (CAS Nos. 79-14-1 and 69-72-7) in SKH-1 mice (simulated solar light and topical application study). Natl Toxicol Program Tech Rep Ser. 2007;524:1–242. 50. Perkins SW, Sklarew EC. Prevention of facial herpetic infections after chemical peel and dermabrasion: New treatment strategies in the prophylaxis of patients undergoing procedures of the perioral area. Plast Reconstr Surg. 1996;98(3):427–433.

53 Chemical Peels KATHERINE HRYNEWYCZ, ALLY-KHAN SOMANI AND MELANIE KINGSLEY

QUESTIONS Q53.1 What depth of peel is generated using superficial, intermediate, and deep chemical peels? What does frosting during a chemical peel indicate? (Pgs. 592, 593x2, Tables 53.1 and 53.2) Q53.2 Why does salicylic acid (SA) penetrate comedones better than other superficial chemical peels? What are additional benefits of SA peels? (Pg. 593) Q53.3 What are the components of Jessner’s peel? (Pg. 593x2, Table 53.3) Q53.4 What are the components of the Baker-Gordon peel and what are two variants of this peel? What are the benefits of each? (Pgs. 593, 594, Table 53.3) Q53.5 What are the four stages of wound healing for deep chemical peels? (Pgs. 594x2, Table 53.4)

Q53.6 Which type of chemical peel can cause cardiotoxicity? (Pgs. 594, 596) Q53.7 What are the three most common categories of indications for chemical peels, as presented in this chapter? (Pg. 594) Q53.8 Considering the risk for either hyperpigmentation or hypopigmentation from chemical peels, (1) what are the primary risk factors, and (2) what are appropriate therapeutic measures? (Pg. 595) Q53.9 Considering scarring from deep chemical peels, what are (1) high-risk anatomic sites, (2) overall risk factors, and (3) appropriate therapeutic measures? (Pg. 596) Q53.10 Which type of chemical peel is safest during pregnancy? (Pg. 596)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R AE Adverse effects AHA α-Hydroxy acid BHA β-Hydroxy acid GA Glycolic acid LHA Lipo-hydroxy acid

Introduction Since ancient times, chemical peels have been used with the goal of skin rejuvenation. The earliest use of aesthetic (chemical) peels was documented by the ancient Egyptians who used a combination of animal oils, salt, alabaster, and sour milk.1 Similar reports were documented by ancient Greeks and Romans. More sophisticated practices evolved in the nineteenth century with von Hebra’s reports on the use of various topical formulations for exfoliation of ephelides and melasma, Fox’s limited reports on the use of phenol for facial ephelides, and Unna’s use of trichloroacetic acid (TCA) peels. In the twentieth century, significant advances were made in the use of phenol by Mackee, with subsequent modifications by Baker and Gordon.2 The introduction of superficial α-hydroxy acid (AHA) peels by van Scott and Yu,3 and combination modifications of TCA peels with solid carbon dioxide (Brody combination),4 Jessner’s solution (Monheit

592

PIH Postinflammatory hyperpigmentation SA Salicylic acid TCA Trichloroacetic acid UV Ultraviolet

combination),5 and 70% glycolic acid (Coleman combination)6 have increased the armamentarium of modern dermatologic treatments. Q53.1 Chemical peels accelerate exfoliation in a controlled manner at various depths within the skin. Each chemical has a unique concentration and mode of action. The physician must choose a type of chemical peel which is safe yet effective for their patient. Chemical peels can be chosen based on the depth of peel they generate, which are categorized as superficial (stratum corneum to basale), medium (papillary dermis), or deep (upper reticular dermis) (Table 53.1). The frosting response seen while using chemical peels represents completion of the reaction as well as indicating the depth of penetration (Table 53.2).

Superficial Chemical Peels Superficial peels produce stratum corneum and upper epidermal sloughing, which improves certain dyschromias. They also

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TABLE Chemical Peels Categorized by Depth of Skin 53.1 Penetration Q53.1

Depth of Penetration Into Skin

Type

593

TABLE Chemical Peel Ingredients Q53.3, Q53.4 53.3

Chemical Peel

Ingredients

Jessner’s solution

14 g resorcinol 14 g salicylic acid 14 g lactic acid (85%) 100 mL ethanol (95%)

Baker-Gordon

3 mL liquid phenol (88%) 2 mL distilled water 8 drops Septisol liquid soap 3 drops croton oil

Superficial Peels Glycolic acid (20%–70%) Jessner’s solution Salicylic acid Lipo-hydroxy acid Solid CO2 slush Retinoic acid TCA (10%–25%)

Chemical Peels

Stratum corneum to stratum basale

Medium-Depth Peels TCA (35%–50%) 35% TCA + Jessner’s solution 35% TCA + 70% glycolic acid 35% TCA + solid CO2

Papillary dermis to upper reticular dermis

Deep Peels Baker-Gordon 88% Phenol >50% TCA

Mid-reticular dermis

β-Hydroxy Acids

TCA, Trichloroacetic acid.

TABLE Frosting Patterns as Related to Depth of 53.2 Chemical Peel Q53.1

Intensity of Frostinga

Skin Findings

Depth of Peel

Level I

Erythema Blotchy frosting

Superficial

Level II

Even white frosting Background erythema

Medium

Level III

Solid white frost Minimal or no background erythema

Deep

aFrosting

in epidermal and dermal thickness have been noted.9 Less frequently used AHA include lactic acid (from sour milk), citric acid (from citrus fruits), malic acid (from apples), mandelic acid (from almonds), and tartaric acid (from grape wine).1 Given their low acidity, all AHA need to be neutralized at the end of the chemical peel with an alkaline solution, such as sodium bicarbonate.

indicates protein denaturation of keratin (keratocoagulation).

stimulate thickening of the epidermis, resulting in a smoother skin texture.7 Superficial peels can be further subcategorized in to very light (stratum corneum) and light (stratum basale).

α-Hydroxy Acids AHA represent a group of weak organic acids derived from fruit (see Chapter 52 for points and counterpoints). One of the most common types of AHA peel is glycolic acid (GA), which is made from sugar cane. Concentrations for GA chemical peels range from 20% to 70%. These peels are typically used over several sessions at weekly or monthly intervals. When used at low concentration (5 seconds), cool extremities, and shiny atrophic skin with loss of hair. The presence of claudication or rest pain is suggestive of arterial insufficiency. The ankle–brachial blood pressure ratio (ankle–brachial index [ABI]) measured by Doppler ultrasound can provide more information on arterial circulation. An ABI of 0.9 or higher is normal, whereas an ABI of 0.5 or less indicates severe arterial disease. Neuropathic ulcers are associated with decreased or altered sensation. They are commonly seen in patients with diabetes mellitus and have high rates of infection. Decubitus ulcers are located at pressure points such as elbows, heels, sacrum, and ischial tuberosities. These ulcers can begin as erythematous plaques or bullae that can belie the depth of injury, which may go to bone. Deep wounds may be associated with purulent to serosanguinous drainage and sinus tract formation.

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TABLE Common Presentation of Ulcers 54.1

Etiology of Ulcer

Presentation

Treatment Approach

Venous

Ulceration often around medial malleolus, accompanying hyperpigmentation, edema, lipodermatosclerosis, hyperkeratosis, atrophie blanche, stasis dermatitis, varicosities.36

Leg elevation, compression, moist dressing, pentoxifylline.11

Arterial

Punched-out ulcers overlying bony prominences (foot), surrounding atrophic, hairless and shiny skin, visible tendons and deep tissue, accompanying claudication/pain, poor peripheral pulses, slow capillary refill time, color change in limbs, decreased ABI.36,37

Modification of risk factors (tobacco use, hyperlipidemia, diabetes, hypertension), aspirin, ticlopidine, clopidogrel, vasodilator drugs, pentoxifylline, cilostazol, naftidrofuryl, propionyl L-carnitines, pain control, limb warmth, hyperbaric oxygen therapy.37,38

Occurs at area of pressure, prior callus, accompanying peripheral neuropathy, peripheral vascular disease, foot deformities.36,39

Off-loading of mechanical stress at wound site, debridement, antibiotic treatment, glucose control.40

Ulceration at bony prominences, predisposing factors include immobility, moisture, increased age, poor nutrition.

Reduction of pressure at area involved, turning and positioning of patients, specialized mattresses.

Viral

Ulceration in the setting of chronic infection with HIV/AIDS, hepatitis C, other viruses.

Treatment of hepatitis C, HIV/AIDS, or other infectious or immunologic cause.

Bacterial

Pyoderma secondary to beta hemolytic Streptococcus pyogenes or Staphylococcus aureus; pustule or punched-out nonhealing ulcer with overlying membrane in cutaneous diphtheria; papule, hemorrhagic blister, malignant pustule leading to shallow ulcer secondary to Bacillus anthracis.41,42

Cultures, appropriate antibiotic therapy.41,42

Mycobacterial, fungal or other

History of recent travel/exposure to pathogens such as parasites, atypical mycobacteria, fungi (sporotrichoid spread with Mycobacterium marinum, sporotrichosis or leishmaniasis).

Appropriate treatment of pathogen.

Calciphylaxis

Occurs in patients with end-stage renal disease, high parathyroid hormone, hyperphosphatemia, high calcium × phosphorous product, hypercalcemia. Initially appears as atypical livedo reticularis with subcutaneous nodules and plaques, later becoming large, painful ulcers with necrosis.43

Decrease calcium in dialysate, reduce phosphate and calcium intake, discontinue vitamin D analogs, elimination of calcium-based phosphate binders, parathyroidectomy, bisphosphonates, sodium thiosulfate, hyperbaric oxygen, tissue plasminogen activator.43

Antiphospholipid antibody syndrome

Livedo racemosa, tender leg ulcers occurring in a variety of sizes, thromboses, anticardiolipin antibodies, lupus anticoagulant, anti-β2 glycoprotein I antibodies, antiphosphotidylserine antibodies.43

Cases with widespread involvement or gangrene, consider anticoagulation.43

Cryoglobulinemia

Painful, symmetric, bilateral, necrotic ulceration with surrounding purpuric skin. May occur in the setting of hepatitis C.44

Plasma exchange, immunosuppressive medications. In hepatitis C-related cryoglobulinemia, treatment to eradicate the virus (i.e., currently lamuvidine) is indicated. Other treatments include corticosteroids, cytotoxic agents, rituximab, plasmapheresis, iloprost, colchicine.44,45

Vasculitis

Ulceration in the distribution of small and medium vessels accompanied by pustules, palpable purpura, urticaria, livedo reticularis, petechiae, subcutaneous nodules and gangrene. There may be accompanying fever, fatigue, and aches.43

Etiology dependent treatment. In isolated cutaneous small vessel vasculitis, conservative treatment may be sufficient. Treatment with dapsone +/− colchicine has been done in mild/moderate disease. In more severe cutaneous small vessel vasculitis particularly with systemic involvement, immunosuppressive or immune modulating medications may be indicated. Treatment with corticosteroids and cytotoxic agents is indicated in medium vessel vasculitis.43

Vascular

Endocrinopathy Diabetes

Physical/Chemical Injury Decubitus ulceration

Infectious

Vasculitis/Vasculopathy

Continued

600

PA RT X

Miscellaneous Topical Drugs

TABLE Common Presentation of Ulcers—cont’d 54.1

Etiology of Ulcer

Presentation

Treatment Approach

Squamous cell carcinoma

Long-standing ulcer in sun-exposed skin, surrounding hyperkeratosis, crusting.41

Appropriate surgical or topical treatment for squamous cell carcinoma.

Basal cell carcinoma

Long-standing, easily friable rodent ulcer in sun-exposed skin.41

Appropriate surgical or topical treatment for basal cell carcinoma.

CTCL

Ulcerations may be accompanied by fissures, patches, plaques, nodules, erythroderma.46

Treatment of CTCL, spot radiation to ulcer site.46

Commonly seen in African-Americans, painful ulcers which may also be associated with priapism and pulmonary hypertension.47

Wet-to-dry dressings, blood transfusion, grafting, zinc, Unna boots, hyperbaric oxygen, arginine butyrate, topical herbal preparations, topical growth factors, pain management.47

Painful digital ulcers may develop secondary to severe sclerosis progressing to gangrene, atrophy and autoamputation.48 May be associated with bacterial infection.

Physical therapy, intravenous iloprost, bosentan, hydrocolloid dressings, absorbent dressing, skin substitutes, antibiotics (topical/systemic).

Pyoderma gangrenosum

Undermined ulcers with surrounding violaceous border, sometimes in association with underlying disease (inflammatory bowel disease, monoclonal gammopathy, hematologic malignancy or paraproteinemia, Behçet disease, Sweet syndrome, hepatitis, HIV, connective tissue disease, rheumatoid arthritis, Takayasu arteritis).41,49

Moisture retentive dressings, pain control, topical tacrolimus, topical corticosteroids, topical cyclosporine for small lesions. In larger lesions, high dose systemic corticosteroids, cyclosporine, thalidomide, methotrexate, tacrolimus, azathioprine, mycophenolate mofetil, cyclophosphamide, chlorambucil, intravenous immunoglobulin, dapsone, granulocyte apheresis, biologics including infliximab, adalimumab, etanercept.49

Neurotic/psychogenic excoriations

Angulated or linear erosions or superficial ulcerations with various stages with accompanying crusts, erosions within reach of digits, there may be surrounding pigmentary alteration and other scars.50

Seek out underlying psychiatric disease and appropriate treatment50

Factitial ulceration

Angulated or linear ulcerations with crusts, erosions at various stages with hyper- or hypopigmentation, may be extensive. Patients deny their role in creating ulcer.

Seek out underlying motivation for creating ulcers, patients with severe self-mutilation may be suicidal.

Malignancy

Hematologic Sickle cell anemia

Connective Tissue Disease Scleroderma

Other Etiologies

CTCL¸ Cutaneous T-cell lymphoma; HIV/AIDS, human immunodeficiency virus/acquired immunodeficiency syndrome.

Pyoderma gangrenosum ulcers are typically very painful and have punched-out or undermined borders with cribriform bases and violaceous discoloration of the surrounding skin. They exhibit pathergy, that is, new ulcers form at the site of minimal trauma. Factitial wounds have asymmetric, sharp, geometric borders with healthy granulation tissue at the bases.

Laboratory Evaluation Q54.2 Laboratory evaluation can include complete blood count (CBC) with white blood cell differential counts; albumin for possible malnutrition; liver enzymes for possible hepatitis; hepatitis virus panel for detection of undiagnosed hepatitis C that can be associated with mixed cryoglobulinemia; rheumatoid factor for possible circulating immune complexes including mixed cryoglobulinemia; and other immunological work-up, including antinuclear antibody (ANA), complement component 3 (C3), complement component 4 (C4), and total hemolytic complement

activity titer (CH50). In addition, evaluation of lupus anticoagulant and antiphospholipid antibodies; general markers of inflammation such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); and hemoglobin (Hgb) A1c for status of diabetes mellitus should be carried out, and other hypercoagulable work-up performed, including protein C, protein S, factor V Leiden, homocysteine, antithrombin III, thrombin gene, and serum protein electrophoresis (SPEP) for blood dyscrasias. Culture. Q54.4 Wound culture and sensitivities can provide invaluable information on bacterial colonization and infection. Bacterial colonization is almost universal for wounds, with the presence of skin commensals on the surface and no overt signs of infection. In lower concentrations, bacteria are known to actually hasten the healing process.6 Once the bacterial count reaches the critical colonization level, wound healing is impeded, without overt signs and symptoms of infection.7 Bacterial counts greater than 105 colony-forming units (CFU) per gram of tissue are known to impede wound healing.8

CHAPTER 54

As the bacterial count continues to rise, organisms cause overt infection accompanied by warmth, erythema, pain, swelling, and leukocytosis. Bacteria secrete a variety of enzymes that degrade the ECM, resulting in delayed healing. Q54.4 Wound cultures can be obtained through a variety of techniques, including superficial swabs, curettes, aspiration, and tissue biopsies. Although swabs are most commonly used and are noninvasive, they often isolate surface bacteria not responsible for infection.9 Tissue obtained with a 3 mm curette on the advancing edge of the wound reliably elucidates the bacteria responsible for slow healing and infection. This maneuver often accelerates wound healing, possibly through biofilm disruption.10 In addition, it offers quantification of bacteria as well as qualitative data. It is relatively noninvasive and correlates with deep tissue biopsy more than wound fluid aspirate and culture swabs. Culture of wound fluid aspirate does not quantify bacterial burden, but it is a noninvasive technique. Deep tissue biopsy is the ‘gold standard’ and reflects the bacterial burden more accurately, but it is invasive and can contribute focally to nonhealing of wounds. In addition to culture, tissue can also be submitted for histological examination and stained for bacteria, fungi, and mycobacteria. Biopsy is also helpful to exclude squamous cell carcinomas (and rarely basal cell carcinomas) in long-standing ulcers. Imaging Studies. Imaging includes Doppler ultrasound to evaluate venous incompetence, with particular attention to perforators. In addition to valvular insufficiency, it can also identify chronic vein wall thickening, or chronic thrombosis suggestive of postthrombotic syndrome. Doppler ultrasound can also be used to evaluate arterial supply to identify arterial stenosis. Biphasic and monophasic wave forms are seen in the setting of arterial stenosis instead of the normal triphasic wave forms. If there is a concern for osteomyelitis, plain films, computed tomography (CT) scans, magnetic resonance imaging (MRI), indium scan/indium white blood cell scan/indium leukocyte imaging/indium-111 scan, and bone biopsy can provide more diagnostic information. In this chapter, we will be discussing primarily the standard practice and management of venous ulcers, as other ulcers (such as arterial ulcers) are beyond the scope of dermatologists and may require surgical intervention. Most of the same wound care principles (aside from debridement) apply to management of pyoderma gangrenosum ulcers; in addition, an underlying autoimmune disorder must be managed with systemic medications.

Venous Ulcer Disease The lower extremities are the most common location for chronic wounds. Venous ulcers alone account for over half of all lower extremity ulcerations, most commonly over the posterior medial malleolus.11 Besides their prolonged healing time, they are commonly prone to recur. The morbidity associated with these ulcers results in high healthcare costs. In addition, decreased productivity accounts for a loss of 2 million working days at a cost of more than US$3 billion annually.12 Patients with chronic ulcerations have chronic disability and diminished quality of life. Larger ulcers are inversely correlated with quality of life, as measured by the Venous Leg Ulcer Quality of Life (VLU-QoL) questionnaire based on Skindex-29.13 Venous ulcers tend to present in patients with chronic venous hypertension, varicose veins, and lower leg edema. Other risk factors associated with venous ulcers include advancing age, family history of venous disease, increased body mass index (BMI), cigarette smoking, prior venous thrombosis, pregnancy, prolonged

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standing, the presence of arteriovenous shunts, and a history of lower extremity trauma or surgical interventions compromising the circulatory system. Studies have shown a strong familial predisposition in the development of varicose veins. In a case–control study of 67 patients and their parents, the risk of developing varicose veins for the children was 90% when both parents were affected, 25% for men and 62% for women when one parent was affected, and 20% if neither parent was affected.14 Pain and swelling are the most common symptoms in patients with venous ulcerations. They are typically worse while standing, or sitting with the feet dependent for prolonged periods of time. Limb elevation alleviates pain and swelling. Pain should be graded at each visit, as increased pain has been associated with infection. Gardner and colleagues15 validated pain, increase in wound size, new areas of breakdown, and odor as signs of high correlation with more than 105 CFU of bacteria per gram of tissue. Q54.3 Venous ulcers have sloping edges with a yellow fibrinous base and have moderate to profuse drainage, exacerbated by the associated edema with pruritus of the surrounding skin. Physical stigmata of venous disease include pitting edema, atrophie blanche, hyperpigmentation because of hemosiderin deposition, varicose veins, stasis dermatitis, and lipodermatosclerosis. Atrophie blanche (which is found in vascular conditions other than livedoid vasculopathy) presents as stellate, ivory-white depressed atrophic plaques surrounded by pigmentation commonly located near the medial malleolus. These areas are vulnerable to future ulceration owing to microvascular thrombotic occlusion and are extremely painful. Lipodermatosclerosis in advanced stages has the characteristic ‘inverted champagne bottle’ appearance of the leg, with sclerotic bound-down skin associated with hyperpigmentation. Pedal pulses should be assessed by palpation or with the hand-held Doppler ultrasound device, as there is a 15% association of arterial insufficiency in patients with venous leg ulcers. Doppler ultrasound, as previously described, is the most commonly used modality to evaluate venous anatomy and incompetence. In addition, photoplethysmography and air plethysmography measure the degree of venous reflux and the efficiency of the calf muscle pump, respectively. These tests have the advantage of assessing the deep venous system in addition to the superficial venous system. Color duplex ultrasound scanning is considered the ‘gold standard’ in evaluating venous anatomy and physiology because of its accuracy, reproducibility, and noninvasive nature. Invasive phlebography is usually reserved for investigation before valvular surgery. Treatment should be aimed at healing the ulcers, preventing their recurrence, and treating the venous insufficiency. Elevation of the legs above heart level for 30 minutes three to four times a day improves the circulation and reduces the edema. However, this is often not practical, and swelling recurs once the legs are in a dependent position. Q54.5 Compression therapy is critical because it decreases edema and counteracts increased hydrostatic pressure in the venous system.

Compression Therapy for Venous Leg Ulcers General Concepts of Compression Therapy. Q54.5 Compression is the cornerstone in the management of venous ulcerations. It increases venous return by assisting the calf muscle pumping effect, venous blood return, lymphatic flow, and cutaneous microcirculation, and it reduces venous reflux.16 However, compression therapy should be avoided in patients without palpable pedal pulses, or an audible signal using a hand-held Doppler device. As stated previously, at least 15% of lower extremity ulcers are mixed venous and arterial in origin.

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Q54.6 Compression can be achieved by various methods. Initially, edema can be reduced with an Unna boot (UB) or short-stretch, long-stretch, or multilayered bandage systems. Once edema has subsided, compression stockings can be used as maintenance. Unna Boot Plus Primary Dressing. An Unna boot (Medicopaste, Graham-Field, Hauppage, New York) is a paste system composed of a bandage impregnated with zinc oxide, calamine, glycerin, and gelatin. A primary dressing (e.g., hydrocolloid, foam, or alginate) is applied to the ulcer. The impregnated bandage is then applied without tension in a circular fashion from the distal foot above the toes up to the tibial tubercle 2.5 centimeters below the knee. The patient should dorsiflex the foot so that it is at a 90 degree angle to the leg. The resultant UB is usually covered with an elastic wrap or support bandage and allowed to dry, forming a semirigid cast. It is changed once or twice weekly based on drainage and edema. A UB is extremely helpful when lower extremity edema is severe, but because it does not accommodate changes in the volume of the leg caused by edema, it needs frequent application. It is relatively contraindicated in patients with active infection. Reported adverse events included dermatitis, allergy, wound maceration, and poor fit. Stretch Bandages. Short-stretch bandages can produce pressures of 18 to 55 mm Hg and can assist the calf muscle pump by compressing the veins and resisting changes in force during walking. This results in low resting and high working pressures.17 Long-stretch bandages, a type of elastic system, provide good working pressures but also higher resting pressures than shortstretch bandages. In general pressures over 40 to 45 mm Hg are poorly tolerated. Multilayer Elastic Bandages. Multilayered elastic bandages are usually applied as three to four layers. All layers are applied with a 50% overlap and provide pressures up to 40 to 45 mm Hg at the ankle. The first layer is an absorbent padding; the second layer is a light conforming wrap; the third and fourth layers are compression layers. Clinical Trials Concerning Compression Therapy for Venous Ulcers. Q54.7 Multiple randomized controlled trials (RCT) have

addressed whether compression improves the healing of venous ulcers. McGuckin and colleagues18 compared healing rates in 160 patients with venous ulcers (80 each in the United States and United Kingdom) before and after implementing treatment guidelines. They noted increased compression compliance with guideline adherence that led to decreased costs and improved healing rates as well as increased quality of life. In a Cochrane Systematic Review of 39 RCT from 1950 to 2008, performed by O’Meara,19 it was noted that compression increases ulcer healing rates compared with no compression. The review also concluded that multilayer systems, especially those consisting of an elastic bandage, are more effective than singlelayer systems. None of the trials demonstrated effectiveness of the four-layer bandage over paste bandage systems, owing to the differences in the paste systems. Duby and coworkers20 randomly assigned 25 legs to the shortstretch (Comprilan) bandage, 25 legs to a 4-layer bandage, and 26 legs to a 3-layer paste boot (UB). Both the 4-layer and the shortstretch bandage resulted in higher healing rates at 12 weeks than a 3-layer paste boot. Marston and colleagues prospectively evaluated 227 patients with 264 leg ulcers, diagnosed either by clinical appearance or by duplex Doppler scan.21 Patients who had an ABI of greater than 0.8 were randomized to either UB covered with an elastic crepe

bandage (Coban) or a 4-layer bandage system (Profore, Smith & Nephew, Largo, Florida). Patients who had an ABI of 0.5 to 0.8 were treated with a 3-layer Profore (Profore Lite). Overall, 69% of the patients were treated with Profore, 18% with UB, and 13% with 3-layer Profore. By week 10, 57% of patients were healed; at week 16, 75% were healed. By the end of 1 year, 96% of all ulcers were healed. Initial ulcer size and moderate arterial insufficiency (ABI 0.5–0.8) were independently associated with delayed healing (P < .01). Ulcers measuring less than 5 cm2 healed significantly faster than ulcers measuring 5 to 20 cm2. No significant differences were noted in healing rate or time based on the compression technique. Meyer and associates22 compared a 3-layer and 4-layer paste bandage system for compression in 133 patients with venous ulcerations. Healing rates for those randomized to the 3-layer system were 80%, compared with 65% in those randomized to the 4-layer system, a statistically significant difference. The 3-layer bandage group healed more rapidly than the 4-layer group: 12 versus 6 weeks. Comparison Between Methods. Q54.7 The UB is most commonly used in the United States, whereas the multilayered compression systems are more commonly used in the United Kingdom. Europe and Australia use short-stretch bandages more frequently.23 Overall, no significant difference was noted between UB and high-compression bandaging systems in healing of the venous ulceration. Compression in general, regardless of the method used, augments the healing of venous ulcerations. Q54.8 Once the initial edema is controlled, compression stockings can be used as maintenance to prevent the recurrence of edema. Compression stockings should exert a minimum of 20 to 30 mm Hg pressure at the ankle to be effective and a higher grade of 30 to 40 mm Hg for active ulceration. Knee-high stockings are better tolerated than thigh-high stockings. Options for patients who have trouble wearing the stockings include custom-fitted stockings, stockings with zipper or Velcro bands, aids for applying the stockings, or pneumatic pumps. The elasticity of stockings diminishes with use and washing, hence they should be replaced about every 6 months.

Wound Bed Preparation Preparation of the wound bed is critical in healing of chronic ulcerations. Q54.9 Based on the recommendations by the International Wound Bed Preparation Advisory Board,24 the TIME protocol was developed. Tissue debridement of nonviable or deficient wound ‘jumpstarts’ re-epithelialization by removing the necrotic tissue and facilitates the formation of healthy granulation tissue. Q54.9 Debridement can be performed in several ways: autolytic via occlusive wound dressings; enzymatic via collagenase (nonpainful, but expensive), papain/urea, trypsin, fibrinolysin/deoxyribonuclease, or bromilase; mechanical with wet to dry dressings; hydrotherapy via whirlpool treatments; biotic with maggots; or surgical debridement with curette or scalpel. Infection or inflammation. Venous ulcers are often colonized by a wide variety of aerobic and anaerobic organisms. The most common bacterium cultured from venous ulcers is Staphylococcus aureus. Persistence of infection and inflammation in chronic wounds despite the use of antimicrobials can be secondary to the existence of a bacterial biofilm. Biofilms are complex multicellular bacterial communities embedded in a matrix of extracellular polymeric substance. The chronic wound contains a mixture of proteins, glycolipids, polysaccharides, and extracellular DNA,

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Assess wound

Clean

Infected

Currette culture

Wet

Dry

Wet

Dry

Hydrogels Cellulose

Silver Iodine Peroxide Bleach

Silver Mupirocin

Deep

Pressure

Impregnated gauze Collagens

Films Hydrocolloids Collagens Offloading

Eschar debridement Mechanical Autolytic Enzymatic

Foams Alginates Hydrofibers

• Fig. 54.1

Choosing a dressing based on wound assessment. (Modified from Lee JC, Kandula S, Sherber NS. Beyond wet-to-dry: a rational approach to treating chronic wounds. Eplasty. 2009;9:e14.)

which furnishes a nearly perfect milieu for biofilm development. Debridement can disrupt the biofilm, which reduces the bacterial burden and facilitates ulcer healing.10 Some dressings, such as Iodosorb, can also help eliminate biofilms.24 Although systemic antibiotic therapy can help ulcers heal, such therapy should be reserved for frank infection, to prevent bacterial resistance. Moisture imbalance. Optimum moisture is necessary for healing of chronic wounds. However, excess fluid can macerate the surrounding tissue and slow epithelial cell migration. On the other hand, drying leads to tissue desiccation, subsequent loss of more tissue and thus impedes wound healing. Occlusive dressings are widely used in wound care as they can provided optimum moisture in the wound and facilitate migration of epithelial cells. Absorptive occlusive dressing should be used if the baseline wound is exudative, (e.g., DuoDerm, Sorbsan) for mild to moderate exudate, and alginate dressing for heavy exudative wounds. Edge of wound. Undermined or rolled edges, often seen in chronic ulcerations, can impede epithelial cell migration, as described above. Debriding the edges can facilitate healing by removing biofilm, as previously mentioned; however, pyoderma gangrenosum must be excluded, as debridement will greatly exacerbate ulcers (pathergy) in this setting.

Wound Care Dressings Used in Venous Ulcerations Wet to dry dressings, although most commonly used, are suboptimal and delay wound healing by removing the migrating epithelium. In addition, they cause pain by exposing sensitive nerve fibers in the wound bed.25 On the other hand, occlusive dressings can provide optimal moisture, promote autolytic debridement and cause little or no pain during dressing changes. Q54.10 Five basic types of occlusive dressing are available: (1) hydrogels (e.g., Curagel, Restore Hydrogel, Nu-Gel), (2) films (e.g., OpSite, Tegaderm), (3) hydrocolloids (e.g., Comfeel, DuoDerm, Tegasorb), (4) foams (e.g., Allevyn, Curafoam, Lyofoam), and (5) alginates (e.g., Sorbsan, Kaltostat, Aquacel). Fig. 54.1 illustrates an outline on how to choose dressings based on the assessment of wound. Venous ulceration often presents with moderate to severe drainage because of high venous hydrostatic pressure and associated edema. Therefore, hydrocolloids, foams, or alginates are indicated because of their absorptive properties. Hydrogels and films are moisture retentive and are uncommonly used in venous ulcers, hence they will not be discussed in detail. For simplicity, we have stratified dressings based on their properties and mechanism of action. Table 54.2 provides an overview of the dressings used in venous ulcers.

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TABLE Dressings Used for Venous Ulcers 54.2

Dressings

Indications

Comments

Examples

Hydrofiber

Wounds with moderate to heavy exudate

Hydroxymethylcellulose fibers are very absorptive of water and permeable. May remain on wound for several days. Silver-containing product available.

Aquacel

Alginates

Wounds with moderate to heavy exudate

Alginate polymer is extracted from seaweed and has a high absorption capacity for water. Maintains granulation tissue formation.

Sorbsan, Kaltostat

Foams

Wounds with light to moderate exudate

Often composed of polyurethane. Permeable and may have adhesive around border. Protects against shear forces. May remain on wound several days. Silver-, methylene blue-, and gentian violet-containing products available.

Allevyn, COPA, Lyofoam, Mepilex, Optifoam, Hydrofera Blue

Hydrocolloids

Wounds with light to moderate exudate

Microgranular suspension of natural or synthetic polymers, e.g., gelatin or pectin. Fluid trapping if used for wounds with heavy exudates. Most have waterproof backing and are therefore impermeable.

Comfeel, DuoDerm, Tegasorb

Hydrogels

Wounds with minimal to light exudate

Composed of cross-linked polymer gels, e.g., polyethylene oxide, and as such adsorbs limited exudate. Excellent for keeping a nonexudative wound moist.

DermaGauze, Flexigel, Geliperm, Tegagel, Vigilon

Hydrocolloids. Hydrocolloids are best used for venous ulcerations with low to moderate amounts of exudate. They are composed of carboxymethyl cellulose, which absorbs the wound exudate and forms a hydrophilic gel, maintaining optimum moisture. They are not recommended for wounds with severe exudates owing to retention of excess fluid in the wound bed leading to periwound maceration. A systematic review was performed for dressings used on venous ulcers. A total of 42 trials were reviewed that had a primary endpoint of healing of the ulcer. The dressing types used were hydrocolloids (n = 23), foams (n = 6), alginates (n = 4), hydrogels (n = 6), and miscellaneous (n = 3). No evidence was found that hydrocolloids were more effective than simple lowadherence dressings when used beneath compression (9 trials with relative risk for healing with hydrocolloid 1.09; 95% confidence interval 0.89–1.34).26 One advantage of hydrocolloids is that they have a prolonged wear time and can be changed every 5 to 7 days based on the wound drainage. Foams. Foams are best used on ulcers with light to moderate exudate. They are made of polymers such as polyurethane or silicone and provide thermal insulation.27 They are permeable to gas, with relatively high moisture vapor transmission rates, yet provide protection against bacteria. When used under compression bandages, foams provide protection from shear forces in addition to absorbing the excess wound fluid. Foams impregnated with methylene blue and gentian violet provide broad-spectrum bacteriostatic protection against methicillin-resistant S. aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and Pseudomonas spp.28 Frequent dressing changes are needed based on the amount of drainage. Alginates. Alginates are highly absorbent dressings used for ulcers with moderate to heavy exudates. They are derived from brown seaweed, Macrocystis pyrifera, Ascophyllum nodosum, and various types of Laminaria. They are composed of calcium and sodium salts of alginic acid, a polymer of mannuronic and glucuronic acids. On contact with wound exudates an ion exchange is initiated, forming

a gelatinous mass. This prevents the lateral wicking of the moisture, and hence prevents wound maceration. They are nonadherent and require a secondary dressing to secure them to the wound bed. Patients should be informed about the formation of gelatinous mass, as it is commonly mistaken as a sign of infection. Alginates also have hemostatic properties and can be used to control bleeding.29 Oasis. Q54.11 Oasis is a naturally occurring ECM derived from the submucosa of the porcine small intestine. It is contraindicated for use in patients with porcine allergies or third-degree wounds. The ECM is incorporated and absorbed into the wound and activates transforming growth factor β1 (TGFβ1), which aids in healing of chronic wounds Integra. Q54.11 Integra is a bilayer matrix wound dressing consisting of cross-linked bovine collagen and glycosaminoglycan with a silicone layer. It requires the application of a secondary dressing to protect and adhere to the wound. Integra stimulates granulation tissue in venous ulcers, in addition to split-thickness grafts and full-thickness thermal injuries. Apligraf. Q54.11 Apligraf is a living, active dermal layer composed of human fibroblasts derived from neonatal foreskin in a bovine type 1 collagen matrix and epidermal layer formed by human keratinocytes. It can produce several growth factors that aid in the healing of venous ulcers.30 It is approved by the US Food and Drug Administration for the treatment of venous ulcers. Apligraf can induce healing of recalcitrant larger and deeper ulcers, but it is expensive and cannot be stored. It is contraindicated for use on clinically infected wounds and in patients with known allergies to bovine collagen. In a multicenter RCT of 275 patients with venous ulcers, patients were randomized to receive compression therapy with or without Apligraf. This study revealed significant healing rates at 6 months in patients treated with Apligraf plus compression therapy compared with those treated with compression alone (63% vs. 49%; P = .02). In addition, the median time to complete wound closure was significantly shorter with Apligraf (61 vs. 181 days).30

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Systemic therapy should be considered as an adjuvant to compression and local wound care. Appropriate systemic antibiotics are indicated in patients with proven infected ulcers. In addition, oral administration of pentoxifylline is effective when used in conjunction with compression therapy and good wound care (see later).

double-blind study by Steed and colleagues,34 recombinant platelet-derived growth factor (PDGF) was studied with placebo in 118 patients with diabetic foot ulcers. Both the groups were treated with recombinant PDGF or placebo for up to 20 weeks. The recombinant PDGF group showed a statistically significant wound healing of 48% versus 25% in the placebo group, which led to the approval of a topical form of the growth factor for diabetic ulcer treatment. Q54.13 Puraply is comprised of purified collagen matrices with a polyhexamethylene biguanide hydrochloride. It is a broadspectrum antimicrobial agent that inhibits microbial colonization and helps to prevent biofilm formation on the wound. Q54.14 Topical re-engineered fibronectin peptides that resist elastase activity have been shown to promote healing in the wound bed. They enhance the ability of PDGF to promote fibroblast growth and survival.35 New biomaterials are being invented and used as bandage substitutes. Novel substances are in the pipeline, including bandages containing antimicrobial peptides.

Pentoxifylline

Bibliography: Important Reviews and Chapters

Q54.12 Oral pentoxifylline, a methyl xanthine derivative, serves as an adjunctive therapy in the treatment of venous ulcers. When combined with compression therapy, pentoxifylline is more efficacious than compression therapy with placebo.31 In addition, pentoxifylline alone is more effective in treating venous ulcers than either placebo or no treatment.31 For the treatment of venous ulcers, pentoxifylline is generally dosed at 400 mg three times daily. Patients taking pentoxifylline should be warned about gastrointestinal adverse effects, including diarrhea, nausea, and indigestion.31 Additional information on pentoxifylline can be obtained from Chapter 33 Vasoactive and Antiplatelet Agents.

Treatment Modalities in Venous Ulcers Green J, Jester R, McKinley R, Pooler A. The impact of chronic venous leg ulcers: a systematic review. J Wound Care. 2014;23(12): 601–612. Kistner RL, Shafritz R, Stark KR, Warriner 3rd RA. Emerging treatment options for venous ulceration in today’s wound care practice. Ostomy Wound Manage. 2010;56(4):E1–E11. Límová M. Active wound coverings: bioengineered skin and dermal substitutes. Surg Clin North Am. 2010;90(6):1237–1255. Word R. Medical and surgical therapy for advanced chronic venous insufficiency. Surg Clin North Am. 2010;90(6):1195–1214.

Periwound Protectants. Excessive moisture, wound fluid pro-

teases, and dressing adhesives can damage the delicate periwound skin. Contact dermatitis is relatively common in venous ulcerations, so avoidance of topical products with common sensitizers is advised. (see Chapter 56 pertaining to topical irritants and allergens). Several periwound products are available that protect the wound from maceration, are anti-inflammatory, and relieve itching. They are composed of petroleum jelly, zinc oxide, calmoseptine, and liquid acrylate. Limited use of topical corticosteroid ointments for coexisting stasis dermatitis can also provide a temporary barrier.

Systemic and Surgical Treatments

Surgical Therapy Traditional Surgical Therapy. Given the lack of specific guidelines, surgical therapy is considered based on the progression of the ulcer. Venous ulcers can extend vertically to tendon and laterally around an extremity in a circumferential manner, prompting the need for autografts. Surgical therapy can also be directed toward treating the underlying chronic venous insufficiency. Historically, ligation followed by stripping of the veins has been the technique to treat venous reflux. Endovascular Ablation Techniques. Q54.12 Endovenous radiofrequency (or laser) ablation has largely replaced ligation as the treatment of choice for venous reflux. It is far less invasive, is an ambulatory procedure, is well tolerated by patients and produces overall good cosmetic results. In endovenous radiofrequency ablation, radiofrequency energy is delivered through a special catheter with deployable electrodes at the tip, whereas laser ablation is performed with a 980 or 1470 nm diode laser. Both procedures cause thermal destruction of the venous tissue, causing the vessel to shrink.32

Growth Factor Therapy Q54.12 Topical growth factors are increasingly being used for venous ulcers. One study demonstrated that venous ulcers improve with topical application of granulocyte–macrophage colony-stimulating factor (GM-CSF).33 In a prospective randomized

Compression in Venous Ulcers O’Meara S, Tierney J, Cullum N, et  al. Four layer bandage compared with short stretch bandage for venous leg ulcers: systematic review and meta-analysis of randomized controlled trials with data from individual patients. BMJ. 2009;338:b1344.

References* 1. Bickers DR, Lim HW, Margolis D, et al. The burden of skin diseases: 2004 a joint project of the American academy of dermatology association and the society for investigative dermatology. J Am Acad Dermatol. 2006;55(3):490– 500. 2. Singer AJ, Clark RAF. Mechanisms of disease: cutaneous wound healing. N Engl J Med. 1999;341:738–746. 10. Kandula S, Zenilman JM, Melendez JH, et al. New frontiers of molecular microbiology in wound healing. In: Sen CK, ed. Advances in Wound Care. vol. 1. New York: Mary Ann Liebert, Inc; 2010. Chapter 49. 11. Valencia IC, Falabella A, Kirsner RS, Eaglstein WH. Chronic venous insufficiency and venous leg ulceration. J Am Acad Dermatol. 2001;44(3): 401–421. 13. Hareendran A, Doll H, Wild DJ, et al. The venous leg ulcer quality of life (VLU-QoL) questionnaire: development and psychometric validation. Wound Repair Regen. 2007;15(4):465–473. 15. Gardner SE, Frantz RA, Troia C, et al. A tool to assess clinical signs and symptoms of localized infection in chronic wounds: development and reliability. Ostomy Wound Manage. 2001;47(1):40–47. 19. O’Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane Database Syst Rev. 2009;21(1):CD000265. 24. Schultz GS, Sibbald RG, Falanga V, et  al. Wound bed preparation: a systematic approach to wound management. Wound Repair Regen. 2003;11(2): Suppl S1–S28. 26. Palfreyman SJ, Nelson EA, Lochiel R, Michaels JA. Dressings for healing venous leg ulcers. Cochrane Database Syst Rev. 2006;3:CD001103.

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28. Saji M, Taguchi S, Uchiyama K, Osono E, Hayama N, Ohkuni H. Efficacy of gentian violet in the eradication of methicillin-resistant Staphylococcus aureus from skin lesions. J Hosp Infect. 1995;31(3):225–228. 36. Fonder MA, Lazarus GS, Cowan DA, Aronson-Cook B, Kohli AR, Mamelak AJ. Treating the chronic wound: a practical approach to the care of nonhealing wounds and wound care dressings. J Am Acad Dermatol. 2008;58(2): 185–206.

37. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. Philadelphia, PA: Elsevier; 2008:1597–1614.

*Only a selection of references are printed here. All other references in the reference list are available online at www. expertconsult.com.

Web References Introduction and Wound Healing 1. Bickers DR, Lim HW, Margolis D, et  al. The burden of skin diseases: 2004 a joint project of the American academy of dermatology association and the society for investigative dermatology. J Am Acad Dermatol. 2006;55(3):490–500. 2. Singer AJ, Clark RAF. Mechanisms of disease: cutaneous wound healing. N Engl J Med. 1999;341:738–746. 3. Franz MG, Steed DL, Robson MC. Optimizing healing of the acute wound by minimizing complications. Curr Probl Surg. 2007;44(11):691–763. 4. Chaine B, Neonato MG, Girot R, Aractingi S. Cutaneous adverse reactions to hydroxyurea in patients with sickle cell disease. Arch Dermatol. 2001;137:467–470. 5. Pieringer H, Stuby U, Biesenbach G. Patients with rheumatoid arthritis undergoing surgery: how should we deal with antirheumatic treatment? Semin Arthritis Rheum. 2007;36:278–286. 6. Pollack SV. The wound healing process. Clin Dermatol. 1984;2:8–16. 7. Cutting KF. Wound healing, bacteria and topical therapies. EWMA J. 2003;3(1):17–19. 8. Robson MC, Krizek TJ. Predicting skin graft survival. J Trauma. 1973;13:213–217. 9. Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2004;39(7): 885–910. 10. Kandula S, Zenilman JM, Melendez JH, et  al. New frontiers of molecular microbiology in wound healing. In: Sen CK, ed. Advances in Wound Care. vol. 1. New York: Mary Ann Liebert, Inc; 2010. Chapter 49. Venous Insufficiency and Venous Ulcers 11. Valencia IC, Falabella A, Kirsner RS, Eaglstein WH. Chronic venous insufficiency and venous leg ulceration. J Am Acad Dermatol. 2001;44(3):401–421. 12. Onegnae K, Phillips T. Leg ulcer management. Emerg Med. 1993;25:45–53. 13. Hareendran A, Doll H, Wild DJ, et al. The venous leg ulcer quality of life (VLU-QoL) questionnaire: development and psychometric validation. Wound Repair Regen. 2007;15(4):465–473. 14. Cornu-Thenard A, Boivin P, Baud JM, De Vincenzi I, Carpentier PH. Importance of the familial factor in varicose disease. Clinical study of 134 families. J Dermatol Surg Oncol. 1994;20(5):318–326. 15. Gardner SE, Frantz RA, Troia C, et al. A tool to assess clinical signs and symptoms of localized infection in chronic wounds: development and reliability. Ostomy Wound Manage. 2001;47(1):40–47. 16. Oduncu H, Clark M, Williams RJ. Effect of compression on blood flow in lower limb wounds. Int Wound J. 2004;1:107–113. 17. Kimbrel PN, Larson-Lohr V. Venous disease. In: Sheffield PJ, Smith APS, Fife CE, eds. Wound Care Practice. Flagstaff, AZ: Best Publishing Company; 2004:267–283. 18. McGuckin M, Waterman R, Brooks J, et al. Validation of venous leg ulcer guidelines in the United States and United Kingdom. Am J Surg. 2002;183:132–137. Compression in Venous Ulcers 19. O’Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane Database Syst Rev. 2009;21(1):CD000265. 20. Duby T, Hofman D, Cameron J, et al. A randomized trial in the treatment of venous leg ulcers comparing short stretch bandages, four layer bandage system, and a long stretch-paste bandage system. Wounds Compend Clin Res Pract. 1993;5:276–279. 21. Marston WA, Carlin RE, Passman MA, Farber MA, Keagy BA. Healing rates and cost efficacy of outpatient compression treatment for leg ulcers associated with venous insufficiency. J Vasc Surg. 1999;30:491–498.

22. Meyer FJ, McGuinness CL, Lagattolla NR, Eastham D, Burnand KG. Randomized clinical trial of 3-layer paste and 4-layer bandages for venous leg ulcers. Br J Surg. 2003;90:934– 940. 23. Davis J, Gray M. Is the Unna’s boot bandage as effective as a four-layer wrap for managing venous leg ulcers? J Wound Ostomy Continence Nurs. 2005;32(3):152–156. Wound Bed Preparation 24. Schultz GS, Sibbald RG, Falanga V, et  al. Wound bed preparation: a systematic approach to wound management. Wound Repair Regen. 2003;11(2):S1–28 (Suppl). 25. Bale S. A guide to wound debridement. J Wound Care. 1997;6:179–182. Treatment Modalities in Venous Ulcers 26. Palfreyman SJ, Nelson EA, Lochiel R, Michaels JA. Dressings for healing venous leg ulcers. Cochrane Database Syst Rev. 2006;3:CD001103. 27. Taylor BA. Selecting wound healing products: choices for longterm care settings. Adv Nurse Pract. 2003;11:63–66. 28. Saji M, Taguchi S, Uchiyama K, Osono E, Hayama N, Ohkuni H. Efficacy of gentian violet in the eradication of methicillinresistant Staphylococcus aureus from skin lesions. J Hosp Infect. 1995;31(3):225–228. 29. Segal HC, Hunt BJ, Gilding K. The effects of alginate and nonalginate wound dressings on blood coagulation and platelet activation. J Biomater Appl. 1998;12(3):249–257. 30. Falanga V, Margolis D, Alvarez O, et  al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Arch Dermatol. 1998;134(3): 293–300. 31. Jill AB, Carroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev. 2007;3:CD001733. 32. Marston W, Tang J, Kirsner RS, Ennis W. Wound healing society 2015 update on guidelines for venous ulcers. Wound Repair Regen. 2016;24:136–144. 33. Jaschke E, Zabernigg A, Gattringer C. Recombinant human granulocyte-macrophage colony-stimulating factor applied locally in low doses enhances healing and prevents recurrence of chronic venous ulcers. Int J Dermatol. 1999;38:380–386. 34. Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity diabetic ulcers. Diabetic ulcer study group. J Vasc Surg. 1995;21(1):71–78; discussion 79–81. 35. Clark RA, Singer AJ, Lin F, Clark RA. Re-Engineering a Fibronectin-Derived Peptide for Topical Treatment of Burns and Chronic Wounds. Presented at the 29th Annual Meeting of the Wound Health Society. San Diego: SAWC Spring/WHS Joint Meeting; 2017. Presentation of Different Ulcers and Treatment 36. Fonder MA, Lazarus GS, Cowan DA, Aronson-Cook B, Kohli AR, Mamelak AJ. Treating the chronic wound: a practical approach to the care of nonhealing wounds and wound care dressings. J Am Acad Dermatol. 2008;58(2):185–206. 37. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. Philadelphia, PA: Elsevier; 2008:1597–1614. 38. Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344(21):1608–1621. 39. Cheer K, Shearman C, Jude EB. Managing complications of the diabetic foot. BMJ. 2009;339:1304–1307. 40. American Diabetes Association. Consensus development conference on diabetic foot wound care: 7–8 April 1999, Boston, massachusetts. American diabetes association. Diabetes Care. 1999;22(8):1354–1360. 41. Mekkes JR, Loots MA, Van Der Wal AC, Bos JD. Causes, investigation and treatment of leg ulceration. Br J Dermatol. 2003;148(3):388–401. 606.e1

606.e2

References

42. Zeegelaar JE, Faber WR. Imported tropical infectious ulcers in travelers. Am J Clin Dermatol. 2008;9(4):219–232. 43. Dean SM. Atypical ischemic lower extremity ulcerations: a differential diagnosis. Vasc Med. 2008;13(1):47–54. 44. Auzerie V, Chiali A, Bussel A, et al. Leg ulcers associated with cryoglobulinemia: clinical study of 15 patients and response to treatment. Arch Dermatol. 2003;139(3):391–393. 45. Iannuzzella F, Vaglio A, Garini G. Management of hepatitis C virusrelated mixed cryoglobulinemia. Am J Med. 2010;123(5):400–408. 46. Lansigan F, Foss FM. Current and emerging treatment strategies for cutaneous T-cell lymphoma. Drugs. 2010;70(3):273–286.

47. Minniti CP, Eckman J, Sebastiani P, Steinberg MH, Ballas SK. Leg ulcers in sickle cell disease. Am J Hematol. 2010;85(10): 831–833. 48. Krieg T, Takehara K. Skin disease: a cardinal feature of systemic sclerosis. Rheumatology (Oxford). 2009;48(suppl 3):S14–S18. 49. Miller J, Yentzer BA, Clark A, Jorizzo JL, Feldman SR. Pyoderma gangrenosum: a review and update on new therapies. J Am Acad Dermatol. 2010;62(4):646–654. 50. Cyr PR, Dreher GK. Neurotic excoriations. Am Fam Physician. 2001;64(12):1981–1984.

55 Agents Used for Treatment of Hyperkeratosis ADAM B. HESSEL, STEPHANIE K. FABBRO, DANA MARSHALL AND JULIO C. CRUZ RAMÓN

QUESTIONS Q55.1 How do salicylic acid and α-hydroxy acids differ regarding lipid solubility and the resultant depth of percutaneous absorption? (Pg. 608) Q55.2 What are some of the mechanisms of salicylic acid leading to keratolytic and desmolytic effects? (Pg. 608) Q55.3 What types of patients may be considered for field therapy for actinic keratosis with 0.5% 5-fluorouracil/10% salicylic acid cream? (Pg. 610) Q55.4 What are several of the key variables in topical salicylic acid use that put patients at risk for significant systemic absorption and resultant salicylism? (Pg. 610) Q55.5 What are the proposed mechanisms by which sulfur has antifungal, antibacterial, and antiparasitic effects? (Pg. 612x3)

Q55.6 What subgroup of scabies patients is most safely treated with 5% to 10% precipitated sulfur? (Pg. 612) Q55.7 By what mechanisms is tar believed to have antiproliferative and anti-inflammatory effects? (Pg. 613x2) Q55.8 What is the evidence, for and against, for the carcinogenicity of tar? (Pg. 614) Q55.9 How do liquor carbonis detergens and crude coal tar differ from a composition and aesthetic standpoint? (Pg. 614) Q55.10 What are several of the chemicals in tar believed responsible for phototoxic effects of tar (and how does this effect relate to the Goeckerman regimen and ‘tar smarts’)? (Pg. 614) Q55.11 By what mechanisms does urea have keratolytic and hygroscopic/humectant properties? (Pg. 614)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R 5-FU 5-fluorouracil FDA US Food and Drug Administration LCD Liquor carbonis detergens PAH Polyaromatic hydrocarbon

SCORAD Scoring Atopic Dermatitis Index UVA Ultraviolet A UVB Ultraviolet B UVR Ultraviolet radiation

Introduction

often shows abnormal keratinization in the form of parakeratosis, compacted orthokeratosis, or a combination of both. While hyperkeratosis is present in many abnormal skin conditions, areas of specialized skin, such as normal palms and soles, have relative hyperkeratosis compared to normal skin of other anatomic sites. For many centuries, the agents discussed in this chapter (i.e., salicylic acid, sulfur, tar, urea) have been used to treat conditions with hypekeratosis and are amongst the first substances ever used to treat skin diseases. Interestingly, the agents discussed in this chapter are not closely related by chemistry or mechanism of action, but rather are related by being known for many years, and in some instances since ancient times, to be beneficial for the treatment of conditions with hyperkeratosis. In this chapter, we will discuss these pharmacologically diverse agents in regard to both historical and modern perspectives.

Substances used to treat hyperkeratosis are frequently referred to as keratolytic agents. These agents significantly reduce the clinical extent of hyperkeratosis. However, some of these keratolytic agents may not be truly ‘lysing’ keratin at the molecular level. In this chapter, the most commonly used topical agents to treat hyperkeratosis are reviewed (Box 55.1). See Chapter 52 for a complete discussion of α-hydroxy acids such as lactic acid and glycolic acid. Hyperkeratosis, from a practical and clinical standpoint, can be defined as the presence of extra keratinaceous material on the skin’s surface and may include scale or other keratinaceous buildup. From a histologic standpoint, hyperkeratosis is typically used to describe an abnormally thick stratum corneum that also

607

608

PA RT X

• BOX 55.1

Miscellaneous Topical Drugs

Agents Used for Treatment of Hyperkeratosis

Salicylic acid Sulfur Tar Urea

O

O

O C

H

H

H

O

H

H

H N

H

N H

H

Urea

H Salicylic acid

• Fig. 55.1

Chemical structure of agents used for treatment of hyperkera-

tosis.

The uniting feature of this chapter is discussion of salicylic acid, sulfur, tar, and urea for the treatment of hyperkeratosis. The byproduct of this effect on hyperkeratosis is of potential benefit for a wide variety of dermatoses, including acne, rosacea, psoriasis, seborrheic dermatitis, verruca, calluses, ichthyosis, and a host of other cutaneous conditions.

Salicylic Acid For over 2000 years, salicylic acid has been used as a topical agent to treat skin disorders.1 Willow bark, which contains salicylic acid, was used by Pliny in the first century ad to treat corns and calluses. In the late 1820s, salicin was isolated from willow bark by Buchner, Brugnatelle, and Fontana, and the process was refined by Leroux. In the 1860s, with the newfound chemical synthesis of salicylic acid, the ability of salicylic acid to soften and exfoliate the stratum corneum was discovered.2

Pharmacology Chemistry. Fig. 55.1 shows the chemical structure of salicylic acid. Salicylic acid is also known as 2-hydroxybenzoic acid or orthohydrobenzoic acid. Salicylic acid and salicylates (which are easily converted to salicylic acid) are present in willow bark, wintergreen leaves, and sweet birch. Salicylic acid can be readily synthesized as well.1,3 Whereas salicylic acid has been described by Kligman4 as a β-hydroxy acid, Yu and Van Scott5 classify salicylic acid as a phenolic aromatic acid. Yu and Van Scott refute the concept of salicylic acid being a β-hydroxy acid because, unlike a true β-hydroxy acid, salicylic acid has both the hydroxyl and the carboxyl groups directly attached to an aromatic benzene ring. In addition, unlike true β-hydroxy acids, the hydroxyl group of salicylic acid exhibits acid properties. The hydroxyl group of true β-hydroxy acids is neutral, and not acidic. An example of a ‘true’ β-hydroxy acid is β-hydroxy butyric acid. Q55.1 In contrast with the α-hydroxy acids (such as lactic acid and glycolic acid), salicylic acid is lipid soluble and therefore is miscible with epidermal lipids and sebaceous gland lipids in hair follicles.

Thus, salicylic acid can interact with the lipids that surround keratinized cells. Salicylic acid is able to interact with multilamellar structures surrounding keratinocytes in the stratum corneum and in hair follicles. In addition, because of its greater lipophilic qualities (compared with α-hydroxy acids), the clinical effect of salicylic acid may be limited to the superficial epidermis. In contrast, the α-hydroxy acids may penetrate deeper into the epidermis and probably into the dermis as well.3 Salicylic acid has a pKa of 2.98. To obtain a significant exfoliative effect, salicylic acid must be formulated at a proper pH to allow enough free acid to be present, compared with the salt form of this drug. Thus, various formulations with concentrations of salicylic acid at a pH close to the pKa give significantly more exfoliation than formulations at any pH significantly greater than the pKa.6 Mechanism of Action Keratolytic and Desmolytic Effects. Q55.2 The mechanism of

salicylic acid as a keratolytic and comedolytic agent is not exactly known.7 Proposed mechanisms include reduction of corneocyte adhesion8 and loosening and detachment of corneocytes.9,10 Salicylic acid, by acting as an organic solvent, may remove the intercellular lipids covalently linked to the cornified envelope that surrounds the cornified cells, creating an environment conducive to discohesion.11 Additionally, organic acids such as salicylic acid extract integral proteins from the desmosomes, including desmogleins, and subsequently destroy the cohesion of epidermal cells.11 Salicylic acid is reported to produce denaturation of membranecrossing glycoproteins and fragmentation of corneodesmosomes. With electron microscopy, fragments of peripheral corneodesmosomes have been observed to be attached to corneocytes on opposite sides. The term ‘desmolytic’ has therefore been proposed as being preferable to the term ‘keratolytic’ in regard to the mechanism of action of salicylic acid. This terminology is proposed because of salicylic acid’s disruption of cellular junctions (desmosome structures), and not lysing or breaking intracellular keratin filaments.12 Human upper arm skin stratum corneum treated with 2% salicylic acid is significantly more easily removed by tape stripping than control sites treated with only the vehicle.13 The increased removal of scale from human skin may be as a result of reduced cohesion between corneocytes. Although salicylic acid appears to have no effect on the mitotic activity of the normal human epidermis,8 studies of pathologic epithelial proliferation in guinea pigs demonstrated a reduction in hyperplasia in viable keratinocytes.14 Salicylic acid causes a more irregular and thinner stratum corneum, without altering epidermal thickness.13 Sunscreen Effects. Salicylic acid and its derivatives can be used as sunscreens (See Chapter 50).15,16 The mechanism of the sunscreen effect is as a result of the benzene ring’s transformation of ultraviolet radiation (UVR) into longer-wave radiation, which is emitted from the skin as heat.17 Anti-inflammatory Effects. Salicylates are also known to possess anti-inflammatory properties. Acetylsalicylic acid, commonly known as aspirin, is well known as an analgesic, antipyretic, and anti-inflammatory agent. Acetylsalicylic acid inhibits prostaglandin biosynthesis.18 Salicylic acid shares some of the anti-inflammatory effects of acetylsalicylic acid.19 The anti-inflammatory effect of salicylic acid is most pronounced at concentrations between 0.5% and 5% (w/w).7

Clinical Use Dermatologic Uses. Box 55.2 lists clinical uses for salicylic acid. Salicylic acid is found in numerous topical preparations, many of which do not require a prescription.20

CHAPTER 55

• BOX 55.2

Salicylic Acid Clinical Uses

Hyperkeratotic Disorders Calluses Corns Hyperkeratosis Ichthyosis (various types) Keratoderma (various types)

Cosmetic/Aesthetic Uses Hyperpigmentation Rejuvenating/peeling

Papulosquamous Dermatoses Psoriasis

Cutaneous Infections Dermatophyte infections Verruca

Dermatitis Cradle cap Seborrheic dermatitis

Other Uses Acne Photoprotection (salicylates) Reduce irritation

Verruca, Molluscum, and Callosities. Salicylic acid is present in a wide variety of wart and callus topical treatments and is often compounded with other keratolytic agents such as lactic acid. Salicylic acid, 2% to 20%, is available in collodion-based paints and gels,20 which dry and form a film from which salicylic acid is absorbed into the skin. In higher concentrations (10%–50%), salicylic acid is used as a plaster that can be cut to fit a wart, corn, or callus.20 A 2006 Cochrane review suggests that salicylic acid in combination with other agents have the most evidence for first-line use in treatment of warts, but as of the time of writing there has been no study comparing salicylic acid, cryotherapy. and placebo.21 A cream containing 5% imiquimod and 15% salicylic acid applied five times per week was more effective than cryotherapy in treating plantar warts, and equally efficacious in treating common and plane warts in children at 3 months, with the former treatment generally better tolerated because of no postprocedural pain.22 A meta-analysis strongly suggested that salicylic acid was particularly efficacious when compounded with 0.5% 5-fluorouracil (5-FU) and was found to be superior to salicylic acid by itself. A modified combination of 2.5% 5-FU and 17% salicylic acid is available in the United States from a compounding pharmacy (WartPeel).21 A 2017 Cochrane Systematic Review analyzing interventions for molluscum contagiosum found that salicylic acid may be a useful adjunctive treatment, although overall quality of the studies found was low.23 A compounded preparation of 10% povidone– iodine and 50% salicylic acid was shown to be effective for all 20 patients with molluscum treated over the course of 26 days.24 Scalp Psoriasis and Seborrheic Dermatitis. Many shampoos contain 2% salicylic acid, often with tar and sulfur1 (see Chapter 51) These shampoos are useful in treating psoriasis, seborrheic dermatitis, and ‘cradle cap’ of the scalp.7 Salicylic acid in ointments and oils, which are usually applied under occlusion, is a useful treatment for thick plaques of scalp psoriasis.25 A Cochrane review recently published studying

Agents Used for Treatment of Hyperkeratosis

609

efficacy of various treatments of scalp psoriasis found there was insufficient data to adequately assess the role of salicylic acid in the treatment of scalp psoriasis. One study that was included in the Cochrane review suggested that topical corticosteroid (TCS) plus salicylic acid was no more efficacious than TCS monotherapy, but the combination tended to lead to complete clearance of psoriatic scalp plaques more often.26 Ichthyosis and Related Conditions. A proprietary compound (Keralyt gel), 6% salicylic acid, 60% propylene glycol, and 20% ethanol, formulated as a gel, is useful in removing thick scales of ichthyosis vulgaris, X-linked ichthyosis, lamellar ichthyosis, and epidermolytic hyperkeratosis, especially when used under occlusion.20 This gel is also useful in various forms of keratoderma, hyperkeratosis palmaris and plantaris of Unna, pityriasis rubra pilaris, and psoriasis. Dermatophyte Infections. The keratolytic effect of the above gel (Keralyt) has been credited with clearing three patients with Trichophyton rubrum infection of the sole.27 Whitfield’s ointment, a time-honored remedy for treatment of tinea infection, contains 6% salicylic acid and 12% benzoic acid in wool fat and petrolatum.1,7 The concentrations of salicylic and benzoic acids can be used at halfstrength to reduce irritation. Whitfield’s ointment has been largely replaced by more effective and elegant preparations. A 3% salicylic acid preparation that also includes benzoic acid is available as Bensal HP in the United States. A compound of 10% salicylic acid and 20% urea has been useful as a means of avulsing toenails nonsurgically.28 Acne. Salicylic acid is believed to have a mild comedolytic effect and is used in acne preparations, including creams, liquid cleansers, astringents, medicated pads, and bar soaps.29 A metaanalysis of 12 randomized controlled trials demonstrated that salicylic acid, when used as a chemical peel in varying concentrations (10%–30%) as a treatment for acne, was comparable in efficacy and tolerability to trichloroacetic acid, glycolic acid, and additional α-hydroxy acids/fruit acids.30 Two studies suggest that glycolic acid is more effective for comedonal acne than Jessner’s solution (14% salicylic acid, 14% resorcinol, and 14% lactic acid in ethanol), with potentially improved tolerability.30,31 Psoriasis (Nonscalp). Salicylic acid is added into topical preparations containing anthralin to prevent its oxidation.32 The original Lassar’s paste contained 2% salicylic acid, 24% zinc oxide, 24% starch, and 50% white soft paraffin.7 Compounds duplicating the formulation of the original Lassar’s paste should always be freshly prepared because on standing the ingredients combine to form zinc salicylate.33 Modern formulations of Lassar’s paste do not contain salicylic acid because of the interaction of salicylic acid and zinc oxide.34 Salicylic acid cannot be incorporated into vanishing creams because salicylic acid ‘cracks’ the cream by decomposing the soap needed to form the appropriate emulsion.35 Although in vitro data suggest that salicylic acid enhances absorption of TCS, this was not confirmed by in vivo studies in animals36 and human subjects.37 However, a study comparing the efficacy of mometasone furoate 0.1% combined with salicylic acid 5% in an ointment, versus a stronger corticosteroid (CS) fluocinonide 0.05% ointment, in the treatment of psoriasis showed that the mometasone furoate–salicylic acid combination was more effective.38 Because of reports of the instability of calcipotriene when mixed with salicylic acid, the compounding of calcipotriene with salicylic acid should be avoided.12 Use in Sunscreens. Salicylic acid and related salicylates can be used as sunscreen ingredients (see Chapter 50). Salicylates maximally absorb ultraviolet B (UVB) in the range 300 to 310 nm.16 Topical salicylic acid, which is frequently used in psoriasis, can interfere with UVB phototherapy for psoriasis.35 Octyl salicylate (2-ethyl hexyl salicylate) and homomenthyl salicylate are used as sunscreen agents in many cosmetic products.16

610

PA RT X

Miscellaneous Topical Drugs

Pruritus and Pain. Salicylic acid is used in antipruritic formulations at a concentration of 1% to 2%.7 Choline salicylate is used as a topical anesthetic for aphthous ulcers.39 Methyl salicylate (found in oil of wintergreen) is used for topical musculoskeletal symptomatic pain relief likely to being a counter irritant.40 Photoaging—Chemical Peels. Salicylic acid has been used as a peeling agent.41,42 Jessner’s solution (14% salicylic acid, 14% resorcinol, and 14% lactic acid in ethanol) is a frequently used superficial peeling agent. Salicylic acid in concentrations of 20% to 30% in a hydroethanolic vehicle (5% water) has gained popularity as a superficial chemical peeling agent for the treatment of acne, photodamage, and hyperpigmentation.41,42 The effect of salicylic acid in chemical peeling procedures is thought to be largely related to epidermal injury, which may be similar to injury caused by other chemical peeling agents, and perhaps even lasers and other ablative techniques.11 A study involving hairless mice showed that a loss of cornified cells was the only morphologic alteration with salicylic acid (7.5%–30%) peeling, followed by activation of the epidermal basal cells and underlying fibroblasts. The authors concluded that following salicylic acid-induced damage to the cornified layer, biochemical and physiologic changes may occur throughout the whole epidermis and in the superficial dermis. These actions may result in a regenerative effect, especially in more photoaged skin.11 A 50% salicylic acid ointment has been used to treat severely photodamaged hands and forearms.43 At lower concentrations of 1% to 2%, salicylic acid is used as an exfoliant to increase corneocyte shedding and improve the appearance of aged skin.44 In a controlled study, a 1.5% to 2% salicylic acid proprietary formulation in a moisturizing vehicle resulted in greater improved facial skin appearance, exfoliation of follicular contents, and increased stratum corneum turnover compared with a bland moisturizer and glycolic acid formulations.45 Salicylic acid has been shown to be safe and effective to use in Fitzpatrick type IV to V skin for postinflammatory hyperpigmentation, whereas more aggressive treatments may aggravate this condition.46 When combined with tretinoin 0.1% cream, salicylic acid peel serves as an even more effective method of treating hyperpigmentation in Fitzpatrick types II to IV without significantly worse tolerability.47 Actinic Keratoses. Q55.3 Salicylic acid 10% may be combined with 0.5% 5-FU in the treatment of diffuse actinic keratoses. This combination is thought to enhance the penetration of 5-FU attributed to the keratolytic properties of salicylic acid. The tolerability and efficacy of such a regimen has been established in a large patient cohort of over 1000 patients, with 70% overall clearance of actinic keratoses on the head and neck.48 The efficacy of such a regimen has also been established in anatomic areas where actinic keratoses tend to be more refractory to treatment, such as the arms. This study of 649 patients (treated with the above combination) demonstrated a clearance rate of 92% for actinic keratoses on the upper extremities.49 The use of this combination has also been applied in a randomized controlled study that included hyperkeratotic actinic keratoses, which, because they are difficult to treat, are not usually included in the clinical trials for field therapy using other agents such as imiquimod 3.75% or ingenol mebutate 0.5%.50 Hyperkeratosis. A delivery system for salicylic acid (multivesicular emulsion) was previously available in the united states as a proprietary product called Salex, which used concentric layers of emulsified liquids in an aqueous medium. The multivesicular emulsion is reported to allow for active ingredients to be ‘layered’ or ‘stacked’, and differs from liposomes. In an open observational uncontrolled trial, the multivesicular emulsion salicylic acid 6% cream applied once in the morning, in combination with desoximetasone or mometasone ointment applied in the evening, was

• BOX 55.3 Salicylic Acid Systemic Toxicity Gastrointestinal Nausea Vomiting

Neurologic Confusion Dizziness Delirium Psychosis Stupor Coma Death

Metabolic Respiratory alkalosis Metabolic acidosis (infants and children) Hypoglycemia

Miscellaneous Tinnitus (an early warning symptom) Hyperventilation

reported to improve psoriasis. The same authors also reported that localized hyperkeratosis (i.e., heels/soles, palms/fingers, and elbows) and keratosis pilaris improved when the multivesicular emulsion 6% salicylic acid cream was applied once in the evening in combination with a morning application of a designated moisturizer.12 As this study was not controlled, the addition of this salicylic acid preparation to provide extra benefit beyond using CS or moisturizers alone for these conditions is not conclusively proven. Hyperhidrosis. Salicylic acid at a concentration of 2% added to a gel containing 15% aluminum chloride hexahydrate (Hydrosal) was reported to be efficacious and less irritating for the treatment of hyperhidrosis than preparations that contained aluminum chloride hexahydrate without salicylic acid.51 Adverse Effects Systemic Absorption—Salicylism. Q55.4 When applied topi-

cally to the skin, salicylic acid is readily absorbed.52 If salicylic acid is applied to erythrodermic skin, it can be detected in the urine within 24 hours.53 Percutaneous absorption of salicylic acid is enhanced by incorporation into hydrophilic ointment,54 tape stripping of the stratum corneum,55 or application under occlusion.56 Systemic toxicity because of percutaneous absorption of salicylic acid is a rare but potentially serious event (Box 55.3). Salicylates in high concentrations are toxic to the central nervous system. Clinical manifestations of salicylate toxicity include nausea, vomiting, confusion, dizziness, delirium, psychosis, stupor, coma, and death.52,57 Tinnitus because of salicylate toxicity is caused by increased labyrinthine pressure and effects on cochlear hair cells, perhaps secondary to vasoconstriction in the auditory microvasculature.52 With salicylate toxicity, there is stimulation of the medullary respiratory center that causes marked hyperventilation and respiratory alkalosis; in infants and children, metabolic acidosis may also occur.52 Signs of salicylate toxicity generally occur when blood concentrations exceed 35 mg/dL. In a 1998 review of the English literature, 32 cases of salicylate toxicity from topical application were found.1 Most of the patients were being treated for psoriasis and ichthyosis. Symptoms of salicylate toxicity appeared early in the course of treatment, frequently

CHAPTER 55

Agents Used for Treatment of Hyperkeratosis

611

TABLE Various Forms of Sulfur 55.1

Form

Color/Consistency

Particle Size

Solubility

Clinical Use

Sublimed sulfur (flower of sulfur)

Yellow powder

Relatively large

Insoluble in water or alcohol

In ointments

Precipitated sulfur (milk of sulfur)

Yellow-white powder

Relatively small

Insoluble in water; slightly soluble in alcohol

In ointments

Colloidal sulfur

Yellow crystalline solid

Relatively smaller

Practically insoluble

Suspended in colloidal solution

Sulfurated potash

Yellow-brown to brown lumps

Relatively large

Soluble in water

In lotions

Sulfurated lime

Clear to orange-colored solution

Particles of polysulfides of calcium may be present

Solution of polysulfides of calcium

In lotions or solutions (e.g., Vleminckx’s solution)

within 2 to 3 days of initiating therapy. Topical application of salicylic acid with concentrations as low as 3%, applied three times daily for 5 days to the entire skin below the neck in an adult, resulted in toxicity.58 In a case of salicylate-induced tinnitus, naproxen was proposed to increase unbound (free) serum salicylic acid by competing for protein binding and hepatic metabolism.52 In two patients, death occurred with topical application of 20.7% salicylic acid to ‘over 50%’ of the body.57 These patients had symptoms of salicylism, although blood salicylate levels were not reported. Systemic Absorption—Hypoglycemia. In addition, salicylates affect glucose utilization. This can lead to hypoglycemia, especially in patients with uremia, in whom there is reduced protein binding of salicylates.59 Contact Allergy. Salicylic acid is considered a weak contact sensitizer,60 with only a few reports of contact sensitization having been recorded.1 Patients with presumed allergic contact dermatitis to salicylic acid preparations may not be allergic to salicylic acid but may be reacting to other components of the preparation. Two patients who had an allergic contact dermatitis to a salicylic acid wart remedy had negative patch-test results to salicylic acid but had positive patch-test results to colophony contained in the same preparation.61

Sulfur Sulfur has been used for medicinal purposes since the time of Hippocrates for the treatment of plague.62 For centuries, sulfur has been used in dermatologic treatment. Antiseptic, antiparasitic, antiacne, and antiseborrheic properties have been attributed to sulfur. The uses of sulfur include treatment of acne, seborrheic dermatitis, rosacea, perioral dermatitis, scabies, and tinea versicolor.

Pharmacology Chemistry. Sulfur is a yellow nonmetallic element. Various preparations of sulfur (Table 55.1) are produced as follows: 1. Sublimed sulfur: This form of sulfur is produced by direct conversion of crude sulfur from solid phase to gas. The vapor is then condensed to yield a fine yellow powder.63 2. Precipitated sulfur: This form of sulfur is produced by boiling sublimed sulfur with lime and water and then adding hydrochloric acid, which results in very fine particles. These particles are significantly smaller than the particles of sublimed sulfur.

The smaller particle size allows for greater interaction between sulfur and skin, thereby enhancing the therapeutic effect.64 3. Colloidal sulfur: This form of sulfur has even smaller particles than precipitated sulfur. This is considered to be the most active form of sulfur, although it is not commonly used in dermatologic products.62 4. Sulfurated potash: This form of sulfur is produced by heating sublimed sulfur with potassium carbonate. 5. Sulfurated lime: This form of sulfur is formed by boiling a suspension of sublimed sulfur, calcium carbonate, and water. This results in the formation of calcium pentasulfide and calcium thiosulfate.65 6. Washed sulfur: This form of sulfur is prepared when sublimed sulfur is treated with ammonia and washed with water to remove impurities such as arsenic.63 The various preparations of sulfur lend themselves to various dermatologic therapeutic uses based on the properties of the form of sulfur. Smaller particle sizes are thought to have greater pharmacologic effect because of the greater area available for sulfur–cutaneous interactions. In addition, water and alcohol solubility, as well as particle size, determine the preferred vehicles for the various sulfur preparations. Both sublimed and precipitated sulfur have US Pharmacopeia official formulations. Precipitated sulfur is the most common form of sulfur used in dermatology.65 Mechanism of Action Keratolytic and Keratoplastic Effects. The precise mecha-

nism of sulfur’s keratolytic effects is unknown.66 The interaction of sulfur with cysteine in keratinocytes probably accounts for the keratolytic effect.62,64 In low concentrations sulfur has keratoplastic (normalizing keratinization and epidermal cell maturation) effects.67 At higher concentrations, sulfur is thought to induce a keratolytic (breaking down the cornified layer) effect. Cysteine combines with sulfur to form cystine and the release of hydrogen sulfide (2 cysteine + sulfur → cystine + H2S).64 Because cystine is a normal constituent of the stratum corneum, at low concentrations sulfur is believed to promote normal keratinization, giving a keratoplastic effect.67 A keratoplastic effect relates to sulfur producing increased, but incomplete, keratinization of the epidermis, few mitoses, and marked vascular dilatation of the dermis. However, sulfur at higher concentrations leads to more hydrogen sulfide, which can break down keratin and can cause dissolution of the stratum corneum.63

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• BOX 55.4 Sulfur Clinical Uses Acne and Related Dermatoses Acne Perioral dermatitis Rosacea

Dermatitis Seborrheic dermatitis

Cutaneous Infections Demodex-induced eruptions Dermatophyte infections Scabies Tinea versicolor Verruca

Antifungal Effects. Q55.5 The antifungal properties of sulfur are related to the formation of pentathionic acid (H2S5O6) by cutaneous bacteria and keratinocytes. Further antifungal activity may also be related to sulfur’s keratolytic action, which causes shedding of infected stratum corneum.68,69 Antibacterial Effects. Q55.5 In addition to its antifungal properties, sulfur has antibacterial properties demonstrated by an inhibitory effect on the growth of Propionibacterium acnes, some Streptococci, and Staphylococcus aureus.70 This antibacterial activity may be a result of the inactivation of sulfhydryl groups contained in bacterial enzyme systems.70 Antiparasitic Effects. Q55.5 The use of sulfur in the treatment of rosacea may be attributed to the killing of Demodex mites, which are implicated as a causative factor in some cases of rosacea. According to a review published in 2004, there have also been several controlled studies showing that the number of Demodex mites was significantly reduced by sulfur. In addition, the clinical symptoms of rosacea were greatly improved when patients were treated topically with Danish ointment, a sulfurbased medication, or other sulfur-inclusive treatments.71 In regard to scabies, the action of sulfur is poorly understood. The formation of hydrogen sulfide and polythionic acid, which are toxic to the mite, in addition to shedding of the stratum corneum through which the mites burrow, may be the mechanisms of action in the treatment of scabies.63,72 Pharmacokinetics. The pharmacokinetics of topical sulfur have yet to be fully characterized. Sulfur penetrates the skin and can be detected in the epidermis within 2 hours, and throughout the skin within 8 hours, after application. However, there are no detectable levels of sulfur in the skin 24 hours after application.70

Clinical Use Dermatologic Uses. The therapeutic uses of sulfur in dermatology

are summarized in Box 55.4.73–79 Various over-the-counter (OTC) preparations contain sulfur and are present in shampoos, cleansers, creams, and other topical forms, to treat seborrheic dermatitis, psoriasis, acne, or rosacea. The keratolytic effect of sulfur may be enhanced by concomitant use with other agents such as salicylic acid.80 Acne and Rosacea. The therapeutic effect of sulfur in acne may not be related to its keratolytic effect but may instead be related to nonspecific ‘irritant’ effects that lead to peeling. Sulfur may not be comedolytic and may even be comedogenic;73,81 however, comedogenicity was not found by Strauss.82

Sulfur has been used topically in combination with sodium sulfacetamide, a sulfonamide-type antibacterial agent. From a historical perspective, the rationale for compounding sulfur with sulfacetamide was possibly a synergistic effect in the treatment of acne, seborrheic dermatitis, and perioral dermatitis. The synergism may relate to sulfur’s desquamative effect in combination with the antibacterial properties of sulfacetamide in a way that is similar to, but better tolerated than, combination therapy with benzoyl peroxide and retinoic acid.83,84 Formulations including hydrocortisone, in combination with sulfur and sulfacetamide, have also been reported to be effective in the treatment of acne, seborrheic dermatitis, and perioral dermatitis. The addition of the hydrocortisone may contribute to the effectiveness as well as tolerability.84 There are a number of proprietary formulations of combined sulfur and sulfacetamide products, available in various forms such as creams, gels, lotions, topical suspensions, masks, cleansers, cleansing cloths, and foams. These products are reported to be effective for the treatment of acne vulgaris, rosacea, and seborrheic dermatitis.70 Many of the products have been commercially promoted to have a unique niche based upon the addition of extra ingredients and/or differing delivery systems. Such unique niches related to extra ingredients include the addition of urea, sunscreen chemicals, tint, and type of sulfur. More unique delivery systems include the mask, foam, and cleansing cloth. However, to our knowledge, no published studies are available comparing added benefit with the use of these extra ingredients or different delivery systems. Sulfur has also been combined with benzoyl peroxide in a proprietary product to treat acne (Sulfoxyl). Sulfur 5%/sodium sulfacetamide 10% lotion was shown to be more effective than metronidazole 0.75% gel for the treatment of rosacea according to Physician’s Global Assessment scores.85 In general, more high quality studies are needed to assess the efficacy of this combination for acne and rosacea. Scabies. Q55.6 Before the availability of permethrin for the treatment of scabies, 5% to 10% precipitated sulfur preparations had been used to treat scabies in pregnant and lactating women, as well as infants. Trials comparing sulfur with lindane and benzyl benzoate have been equivocal, suggesting that there is no superior option among these choices.86 In addition, there are no well-designed studies regarding the efficacy and toxicity of sulfur and permethrin in the therapy of scabies.62 Adverse Effects. Fatal toxicity after sulfur was applied to large areas of the skin of infants has been reported rarely.87 In addition, allergic contact dermatitis to sulfur has been described.88,89 The limiting factor of the use of sulfur is its offensive odor, which is similar to the odor of rotten eggs.65 Patients who were treated with sodium sulfacetamide/sulfur cream were more likely to experience adverse cutaneous reactions than those treated with metronidazole or azelaic acid for rosacea, incurring higher costs of treatment.90

Tar The use of tar to treat skin diseases dates back nearly 2000 years. The Greek physician Pedanius Dioscorides (c. 20 ad) used tar preparations in the form of asphalt to treat cutaneous afflictions.91 In 1925, Goeckerman introduced the use of crude coal tar and UV light for the treatment of psoriasis.92

Pharmacology Chemistry. Tar is the dry distillation product of organic matter heated in the absence of oxygen. Tar preparations of dermatologic

CHAPTER 55

importance are derived from three main organic sources: bituminous coal, wood, and marine fossils. Crude coal tar, the most widely used form of tar in dermatology, is produced from gases obtained during the distillation of coal at temperatures ranging from about 900°C to 1200°C. The solid distillation byproduct of this chemical process is coke, which is used to manufacture steel. Condensation of these gases to their liquid phase, and subsequent ammonia extraction, produces crude coal tar, a thick, dark, odorous liquid. Crude coal tar is composed of a complex mixture of thousands of individual organic components, which include polyaromatic hydrocarbons (PAH), phenols, and nitrogen bases. Fractional distillates obtained at different temperatures produce coal tars of different color, smell, consistency, and organic composition. Also, an alcohol extract of coal tar emulsified with polysorbate (Tween 80) yields a more cosmetically acceptable product known as liquor carbonis detergens (LCD).93 Wood tar preparations are derived from distillation at temperatures not exceeding 700 degree celcius of trees such as birch (Oleum rusci), beech, juniper (Cade oil), or pine. They have fewer carcinogenic agents, such as pyridines and anthracene, than coal tar, but are more irritating and toxic because of higher phenol absorption properties. Bituminous tar, also known as sulfonated shale oil (ichthyol), is derived from distillation of marine fossil sediments and natural rock at temperatures ranging from 150°C to 500°C. Subsequent chemical degradation of byproducts is accomplished using ammonia and sulfuric acid. Bituminous tar preparations can be light or dark in color, depending on the manufacturing temperature. Mechanism of Action. The mode of action of tar is not well understood. Because of its inherent chemical complexity, tar is not pharmacologically standardized, and the specific therapeutic activity of the components is not known. Antiproliferative Effects. Q55.7 Nonetheless, tar has conclusive antiproliferative effects on the epidermis. Studies by Lavker and colleagues94 demonstrated a progressive thinning of the epidermis that follows a transient epidermal hyperplasia attributed to primary irritation. Tar appears to exert its actions through suppression of deoxyribonucleic acid (DNA) synthesis and consequent reduction of mitotic activity in the basal layer of the epidermis.95–98 In combination with UV light, coal tar reduces epidermal proliferation more effectively than noted with either treatment modality alone.98 Other Effects of Tar. In addition to its antiproliferative action, shale tar (bituminous tar) has anti-inflammatory activity caused by inhibition of chemotaxis of neutrophils attributed to leukotriene B4 and C5a.99,100 Listemann101 also demonstrated fungicidal properties of shale tar, but the antifungal mechanism of action is not known.

Clinical Use Table 55.2 lists clinical uses of tar. Dermatologic Uses. Tar preparations are a useful topical therapy in the management of inflammatory skin diseases, especially psoriasis vulgaris, atopic dermatitis, seborrheic dermatitis, and eczematous dermatitides. Psoriasis. Coal tar in combination with UVR for psoriasis (known as the ‘Goeckerman regimen’) has been diversified and customized according to institutional experience. The use of modified regimens using LCD or other tars is generally thought to be beneficial. The original regimen was based on topical daily use of crude coal tar, followed by gradually increasing doses of UV light.92 Tar can also be used topically without UV light to treat psoriasis.

Agents Used for Treatment of Hyperkeratosis

613

TABLE Tar Clinical Uses 55.2

Dermatosis

Coal Tar

Wood Tara

Shale Tara

Psoriasis

X

X

X

Atopic dermatitis

X

Seborrheic dermatitis

X

Tinea versicolor

X

Yeast or dermatophyte infections

X

Vitiligo

X

Pruritus

X

aBoth

X

wood tar and shale tar are useful for other inflammatory dermatoses (see text).

A Cochrane review recently published studying efficacy of various treatments of scalp psoriasis found there was insufficient data to adequately assess the role of tar in the treatment of scalp psoriasis.22 Topical tar as monotherapy has been found to be less effective in the treatment of psoriasis than many other topical therapies in recent reviews, including TCS and vitamin D analogs, and is included primarily for historical interest.101 Seborrheic Dermatitis. Tar shampoos are commonly used to treat seborrheic dermatitis of the scalp. Sulfonated shale oils are of interest for their use in seborrheic dermatitis and other inflammatory dermatoses. In addition, these shale oils have antifungal properties against yeast, dermatophytes, and hyphomycetes.102 Use of Tar in Compounding. Coal tar, in concentrations up to 20% (usually in the range of 5%–20%), can be compounded in creams, ointments, and pastes. Coal tar is frequently compounded with salicylic acid. In addition, tar preparations are available as bath soaks, shampoos, soaps, and topical emulsions. Adverse Effects Possible Carcinogenesis. Q55.7 The safety of tar, especially

coal tar, has been a matter of debate for decades. In the United States, the US Food and Drug Administration (FDA) scrutinized topical tar use because of concerns about carcinogenic potential, but declared tar effective and safe.103 Skin cancer has been induced in mice exposed to coal tar preparations.104 However, clinical studies in numerous patients who have used topical tar preparations chronically demonstrated that the skin cancer incidence in these patients was no different from that in the general population.105–108 In contrast, other mostly anecdotal case reports or case series reported skin cancer occurrence in patients who used tar preparations.109–111 However, in patients with psoriasis who received extensive treatment with tar or UVR, the incidence of skin cancer was increased.112 The relative contributions of the UVR and the tar components to this carcinogenesis is unknown. A 2006 study showed the potential for Goekerman therapy to cause genotoxic effects, with increased urinary mutagenicity and chromosomal aberrations of peripheral lymphocytes in blood samples detected at the end of treatment and lessening after treatment.113 Again, the relative contributions of the tar and UVR to cause these genotoxic effects are unknown. In addition, conducting well-designed studies in the future to determine the relationship, if any, between extracutaneous malignancy and dermatologic use of tar has been recommended.114

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Scrotal squamous cell carcinoma in association with tar exposure is a well-known occupationally induced cancer. However, the use of protective clothing, better hygiene, and less scrotal exposure to carcinogens made tar-induced scrotal squamous cell carcinoma primarily of historical significance only.115 Nonetheless, there are multiple reports in the urology literature referring to the use of tar in the genital area and the subsequent occurrence of scrotal carcinoma.116–118 Q55.8 The cancer potential of tar has been linked to its carcinogen content. The major carcinogenic agents in tar are PAH such as benzapyrene and anthracene, along with pyridines. Coal tar is rich in all of these carcinogenic agents; wood tar is rich in PAH. Bituminous tar (shale oil) has comparatively low levels of these carcinogenic agents.119 Aesthetic Issues. Q55.9 A major disadvantage of the use of coal tar is poor compliance. Crude coal tar is unattractive for use because of its unwelcome smell, appearance, and capacity to stain clothing and other items. Consequently, crude coal tar has been modified in several ways, such as fractional distillates and LCD. LCD appears more therapeutically effective than fractional distillates but is therapeutically inferior to crude coal tar.119 Patient acceptance of LCD tends to easily exceed that of other forms of tar. Phototoxicity. Q55.10 Phototoxicity is an adverse effect (AE) of coal tar that may also be responsible (at least in part) for the therapeutic effect of the Goeckerman regimen. There are several phototoxic components in coal tar, including anthracene, fluoranthene, phenanthrene, benzapyrene, and acridine.120 In addition, wood tar and bituminous tar do not photosensitize and are more cosmetically attractive than coal tar. It is of interest that ‘tar smarts’ (phototoxicity with natural sunlight and inadvertent tar exposure) is caused by UV radiation wavelengths in the UVA spectrum. Contact Allergy. In addition, tar products can induce different types of contact allergy. Phototoxic and photoallergic reactions to coal tar products have been reported.121 The phototoxic dermatitis can result in a poikiloderma.122 More often, contact dermatitis appears to occur with wood tar, which may cross-react with colophony, balsam of Peru, and turpentine.122,123 Other Adverse Effects of Tar. The acute toxic potential of tar, particularly wood tar, has been linked to phenol content. But newer tar products have been manufactured with reduced phenol content, minimizing the risk for phenol toxicity.119 Irritant reactions to tar can occur as well. Tar can also produce pruritus, folliculitis, comedones, acneiform eruptions, keratoses (tar warts), and keratoacanthomas.122

Urea In 1828, the German chemist Frederich Wohler was the first to synthesize an organic compound and as a result originated the discipline of organic chemistry. The compound he synthesized was urea.124 Urea is found in urine. Ancient Babylonians instilled urine into wounds. This unusual practice may have had some utility because of the antimicrobial properties of urea.125 For many years, urea has been used effectively in topical preparations as a moisturizing, hygroscopic (the ability to attract water), antimicrobial, and keratolytic agent. For purposes of this section, the terms ‘hygroscopic’ and ‘humectant’ both refer to the property of a substance to attract water.

Pharmacology Chemistry. Fig. 55.1 shows the chemical structure of urea. Urea is produced by dehydration of ammonium carbamate (NH2CO2NH4) at high temperature and pressure. Ammonium

carbamate is obtained by reaction of ammonia and carbon dioxide. The molecule of urea is bipolar, rendering the molecule highly water soluble and capable of ionic interactions with salt solutions. This latter property causes an increase in the water-binding capacity of urea when mixed with sodium chloride.126 The ability of urea to retain water is especially illustrated by sharks. Sharks generate and preserve high concentrations of urea in their tissues. These levels of urea slightly surpass the salt concentration of seawater, preventing dehydration by osmosis and eliminating the need for sharks to swallow seawater.127 Urea is the end product of the catabolism of animal proteins. Hence, urea is not an energy source for most pathogenic bacteria and does not promote pathogenic bacterial growth. Mechanism of Action General Effects of Urea. Urea has various pharmacologic and

chemical actions relevant to the skin. Urea is an antimicrobial agent, protein solvent and denaturant, and enhancer of protein water-binding capacity. Urea has been shown to inhibit the growth of some microorganisms.128 In addition, urea enhances percutaneous absorption of various chemicals and pharmaceutical agents.128 Keratolytic and Hygroscopic/Humectant Effects. Q55.11 Topically applied urea is capable of incorporating itself into the cornified layer of the epidermis by breaking hydrogen bonds and reaching the interior of epidermal keratins.129 Because of urea’s properties of high water solubility and low water vapor pressure, urea is capable of absorbing water from the atmosphere in a highhumidity environment. With urea, the hydrated stratum corneum preserves its flexibility and softness.130 Loden131 demonstrated that urea-containing moisturizers reduce transepidermal water loss and increase skin hydration. Urea also enhances penetration of various topically administered drugs, including some TCS.132 High concentrations of urea dissolve proteins and can be used as a denaturant.128 The ability of urea to macerate dystrophic nails has been attributed to a ‘proteolytic effect,’125 but other authors attributed the maceration to the hydrating properties of urea.133 A dead frog immersed in a saturated solution of urea becomes macerated and disintegrated in a few hours. Maceration of fullthickness dermatitic skin occurs at more than 20% concentration of urea in water.128 Ultimately, the keratolytic mechanism of urea is not known. However, the bipolar molecular structure gives the urea molecule keratin dispersing and denaturing capabilities without disrupting the epidermal water barrier.134 Some authors dispute the categorization of urea as a keratolytic agent because urea does not cause direct metabolic or enzymatic alterations of the epidermis. However, urea promotes keratolysis by exerting physical alterations such as improved hydration in the cornified layer.13,129,130 Urea’s water solubility and binding capacity give it the emollient and hygroscopic characteristics, leading to increased desquamation of corneocytes.

Clinical Use Dermatologic Uses Xerosis and Hyperkeratosis. Table 55.3 lists clinical uses of

urea. Urea is effective for conditions associated with dry skin, including atopic dermatitis, xerotic eczema, keratosis pilaris, ichthyosiform dermatoses, and keratodermas.135 There is low to moderate evidence showing that urea improves symptoms of atopic dermatitis more than placebo, vehicle, or no moisturizer, but with potentially more skin irritation.136 Topical urea in concentrations

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Urea 10%–25%

Urea 40%–50%

Pharmacologic Properties

615

stinging and irritation. These AE are related to the high acidity of many preparations (usually pH ≤3.0).135 However, new stabilized preparations claim less acidity and consequently less skin irritation.

TABLE Urea Clinical Uses 55.3

Concentration

Agents Used for Treatment of Hyperkeratosis

Dermatoses Treated

Moisturizing Hydroscopic Antipruritic Keratolytic (mild)

Xerosis Atopic dermatitis Xerotic dermatitis Keratosis pilaris Keratodermas Ichthyosis Hyperkeratosis

Chemical hygroscopic keratolysis

Calluses Chemical avulsion of dystrophic nails Hyperkeratosis

of 10% and 20% can be used as an emollient and mild keratolytic agent.135 As a water-in-oil emulsion, urea was found to effectively reduce the Scoring Atopic Dermatitis Index (SCORAD) for patients with atopic dermatitis, similar to a linoleic acid water-inoil emulsion.137 There is also one double-blind study showing the antipruritic qualities of urea.138 Until recently, most of the commercially available OTC topical cream and lotion preparations of urea typically had concentrations ranging from 10% to 25%. More recently, products have become available with urea concentrations up to 50%. Also, gel, applicator stick, and medicated pad formulations of urea, as well as preparations of lactic acid combined with urea, have become commercially available. Preparations containing 40% to 50% urea can be used topically for treatment of calluses and other forms of localized hyperkeratosis. Chemical Nail Avulsion. A compound of 40% urea, 20% anhydrous lanolin, 5% white wax, and 35% white petrolatum, under occlusion, can be used for chemical avulsion of dystrophic nails.125,139 The compound was subsequently modified to 40% urea, 5% white beeswax (or paraffin), 20% anhydrous lanolin, 25% white petrolatum, and 10% silica gel type H. There are very specific compounding instructions for these nail avulsion compounds.140 However, a similar rate of success was found in the chemical avulsion of dystrophic nails when an emollient cream under occlusion was compared with a 40% urea compound under occlusion.133 Although 40% urea compounds are not effective for the avulsion of normal (i.e., nondystrophic) nails, 10% salicylic acid with 20% urea in a topical compound can be effective for avulsing symptomatic nondystrophic nails,28 although the efficacy of the urea and salicylic acid combination for normal nail avulsion has been disputed.140 The newer commercially available formulations of urea with higher (up to 40%–50%) concentrations may also be helpful with nonsurgical avulsion of dystrophic nails. Less Common Uses of Urea. Unusual uses of urea include intralesional injection for treatment of basal cell and squamous cell carcinoma as well as topical application for superficial basal cell carcinoma and actinic keratosis.141 Urea has also been used as an adjunct for wound healing.142 Adverse Effects. Topical urea preparations can cause irritant reactions and maceration, which are more likely with the higher concentration products and especially if used under occlusion. Application of urea in excoriated or fissured skin can produce

Acknowledgment The authors would like to acknowledge Dr. Andrew N. Lin for his very important contributions to this chapter as a contributing author of the previous editions and to dermatology as a whole. Dr. Lin’s published articles on the history and uses of Salicylic Acid, Tar, and Sulphur continue to be invaluably educational, and he will be remembered and missed as a great scholar of these subjects of dermatopharmacology.

Bibliography: Important Reviews and Chapters Salicylic Acid Brackett W. The chemistry of salicylic acid. Cosmet Derm. 1997;10 (suppl 4):5–6. Chen X, Wang S, Yang M, Li L. Chemical peels for acne vulgaris: a systematic review of randomised controlled trials. BMJ Open. 2018;8(4):e019607. Draelos ZD. Rediscovering the cutaneous benefits of salicylic acid. Cosmet Derm. 1997;10(suppl 4):4. Lin AN, Nakatsui T. Salicylic acid revisited. Int J Dermatol. 1998;37(5): 335–342. van der Wouden JC, van der Sande R, Kruithof EJ, Sollie A, van Suijlekom-Smit LW, Koning S. Interventions for cutaneous molluscum contagiosum. Cochrane Database Syst Rev. 2017;5:CD004767. Sulfur Gupta AK, Nicol K. The use of sulfur in dermatology. J Drugs Dermatol. 2004;3:427–431. Lin AN, Reimer RJ, Carter DM. Sulfur revisited. J Am Acad Dermatol. 1988;18:553–558. Strong M, Johnstone P. Interventions for treating scabies. Cochrane Database Syst Rev. 2007;3:CD000320. van Zuuren EJ, Fedorowicz Z, Carter B, van der Linden MM, Charland L. Interventions for rosacea. Cochrane Database Syst Rev. 2015;4:CD003262. Tar Chan CS, Van Voorhees AS, Lebwohl MG, et  al. Treatment of severe scalp psoriasis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2009;60(6):962–971. Lin AN, Moses K. Tar revisited. Int J Dermatol. 1985;24(4):216–219. Paghdal KV, Schwartz RA. Topical tar: back to the future. J Am Acad Dermatol. 2009;61(2):294–302. Urea Banerjee PK, Choudhury AK, Panja SK. Topical urea in dermatology. Indian J Dermatol. 1990;35(1):17–24. van Zuuren EJ, Fedorowicz Z, Christensen R, Lavrijsen A, Arents BWM. Emollients and moisturisers for eczema. Cochrane Database Syst Rev. 2017;2:CD012119.

References* 1. Lin AN, Nakatsui T. Salicylic acid revisited. Int J Dermatol. 1998;37(5):335– 342. 2. Draelos ZD. Rediscovering the cutaneous benefits of salicylic acid. Cosmet Derm. 1997;10(suppl 4):4. 3. Brackett W. The chemistry of salicylic acid. Cosmet Derm. 1997;10(suppl 4):5–6.

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5. Yu RJ, Van Scott EJ. Salicylic acid: not a beta-hydroxy acid. Cosmet Derm. 1997;10:27. 7. Draelos ZD. Salicylic acid in the dermatologic armamentarium. Cosmet Derm. 1997;10(suppl 4):7–8. 66. Lin AN, Reimer RJ, Carter DM. Sulfur revisited. J Am Acad Dermatol. 1988;18(3):553–558. 70. Gupta AK, Nicol K. The use of sulfur in dermatology. J Drugs Dermatol. 2004;3(4):427–431. 93. Lin AN, Moses K. Tar revisited. Int J Dermatol. 1985;24(4):216–218.

114. Paghdal KV, Schwartz RA. Topical tar: back to the future. J Am Acad Dermatol. 2009;61(2):294–302. 131. Loden M. Urea-containing moisturizers influence barrier properties of normal skin. Arch Dermatol Res. 1996;288(2):103–107. 135. Banerjee PK, Choudhury AK, Panja SK. Topical urea in dermatology. Indian J Dermatol. 1990;35(1):17–24.

*Only a selection of references are printed here. All other references in the reference list are available online at www.expertconsult.com.

Web References Salicylic Acid—Pharmacology 1. Lin AN, Nakatsui T. Salicylic acid revisited. Int J Dermatol. 1998;37(5):335–342. 2. Draelos ZD. Rediscovering the cutaneous benefits of salicylic acid. Cosmet Derm. 1997;10(suppl 4):4. 3. Brackett W. The chemistry of salicylic acid. Cosmet Derm. 1997;10(suppl 4):5–6. 4. Kligman AM. Salicylic acid: an alternative to alpha-hydroxy acids. J Geriatr Dermatol. 1997;5:128–131. 5. Yu RJ, Van Scott EJ. Salicylic acid: not a beta-hydroxy acid. Cosmet Derm. 1997;10:27. 6. Smith WP, Smith W. Hydroxy acids and skin aging. Soap Cosmet Chem Spec. 1993;69:54–76. 7. Draelos ZD. Salicylic acid in the dermatologic armamentarium. Cosmet Derm. 1997;10(suppl 4):7–8. 8. Roberts DL, Marshall R, Marks R. Detection of the action of salicylic acid on the normal stratum corneum. Br J Dermatol. 1980;103(2):191–196. 9. Marks R, Davies M, Cattell A. An explanation for the keratolytic effect of salicylic acid. J Invest Dermatol. 1975;64:283. 10. Davies M, Marks RL. Studies on the effect of salicylic acid on normal skin. Br J Dermatol. 1976;95(2):187. 11. Imayama S, Ueda S, Isoda M. Histologic changes in the skin of hairless mice following peeling with salicylic acid. Arch Dermatol. 2000;136(11):1390–1395. 12. Del Rosso J. Pharmacotherapy update: current therapies and research for common dermatologic conditions. The many roles of topical salicylic acid. Skin Aging. 2005;13:38–42. 13. Lodén M, Boström P, Kneczke M. Distribution and keratolytic effect of salicylic acid and urea in human skin. Skin Pharmacol. 1995;8(4):173–178. 14. Weirich EG, Longauer JK, Kirkwood AH. Dermatopharmacology of salicylic acid. II. Epidermal anti-hyperplastic effect of salicylic acid in animals. Dermatologica. 1975;151(6):321–332. 15. U.S. Food and Drug Administration. Sunscreen drug products for over-the-counter human drugs; proposed safety, efficacy and labeling conditions. Federal Register. 1978:38206. 16. Shaath NA. Evolution of modern chemical sunscreens. In: Lowe NJ, Shaath NA, eds. Sunscreens Development, Evaluation and Regulatory Aspects. New York: Marcel Dekker; 1990:3–35. 17. Lowe NJ. Sun protection factors: comparative techniques and selection of ultraviolet sources. In: Lowe NJ, ed. Physicians Guide to Sunscreens. New York: Marcel Dekker; 1991:161–165. 18. Insel PA. Analgesic-antipyretics and anti-inflammatory agents: drugs employed in the treatment of rheumatoid arthritis and gout. In: Gilman AG, Rall TW, Nies AS, et al., eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. New York: Pergamon Press; 1990:644–653. 19. Wierich EG, Longauer JK, Kirkwood AH. Dermatopharmacology of salicylic acid. III. Topical contra-inflammatory effect of salicylic acid and other drugs in animal experiments. Dermatologica. 1976;152(2):87–99. Salicylic Acid—Clinical Use 20. United States Pharmacopeial Convention I. Salicylic acid: topical. In: Drug Information for the Health Care Professional. Rockville, MD: United States Pharmacopeial Convention; 1996:2607–2611. 21. Gibbs S, Harvey I. Topical treatments for cutaneous warts. Cochrane Database Syst Rev. 2006;3:CD001781. 22. Stefanaki C, Lagogiani I, Kouris A, Kontochristopoulos G, Antoniou C, Katsarou A. Cryotherapy versus imiquimod 5% cream combined with a keratolytic lotion in cutaneous warts in children: a randomized study. J Dermatolog Treat. 2016;27(1):80–82.

23. van der Wouden JC, van der Sande R, Kruithof EJ, Sollie A, van Suijlekom-Smit LW, Koning S. Interventions for cutaneous molluscum contagiosum. Cochrane Database Syst Rev. 2017;5:CD004767. 24. Ohkuma M. Molluscum contagiosum treated with iodine solution and salicylic acid plaster. Int J Dermatol. 1990;29(6):443–445. 25. Larko O. Problem sites: scalp, palm and sole, and nail. Dermatol Clin. 1995;13(4):771–777. 26. Schlager JG, Rosumeck S, Werner RN, et al. Topical treatments for scalp psoriasis. Cochrane Database Syst Rev. 2016;2:CD009687. 27. Baden HP, Alper JC. A keratolytic gel containing salicylic acid in propylene glycol. J Invest Dermatol. 1973;61(6):330–333. 28. Buselmeier TJ. Combination urea and salicylic acid ointment nail avulsion in nondystrophic nails: a follow up observation. Cutis. 1980;25(4):397. 405. 29. Leyden JL, Shalita AR. Rational therapy for acne vulgaris: an update on topical treatment. J Am Acad Dermatol. 1986;15(4Pt2):907–915. 30. Chen X, Wang S, Yang M, Li L. Chemical peels for acne vulgaris: a systematic review of randomised controlled trials. BMJ Open. 2018;8(4):e019607. 31. In Jae J, Dong Ju H, Dong Hyun K, Yoon MS, Lee HJ. Comparative study of buffered 50% glycolic acid (pH 3.0) + 0.5% salicylic acid solution vs Jessner’s solution in patients with acne vulgaris. J Cosmet Dermatol. 2018;17(5):797–801. 32. Christophers E, Sterry W. Psoriasis. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al., eds. Dermatology in General Medicine. New York: McGraw-Hill; 1993:489–514. 33. Polano MK. Skin Therapeutics: Prescription and Preparation (Materia Medica Dermatologica). Amsterdam: Elsevier; 1952:57–58. 111. 34. Young E, Weiffenbach N. About the conversion of salicylic acid into zinc salicylate in ointment and pastes containing both zinc oxide and salicylic acid. Dermatologica. 1959;118:74. 35. Harvey SC. Topical drugs. In: Osol A, ed. Remington’s Pharmaceutical Sciences. Easton, PA: Mack; 1975:724–725. 36. Wester RC, Noonan PK, Maibach HI. Effect of salicylic acid on the percutaneous absorption of hydrocortisone: in  vivo studies in the Rhesus monkey. Arch Dermatol. 1978;114(8): 1162–1164. 37. Täuber U, Weiss C, Matthes H. Does salicylic acid increase the percutaneous absorption of diflucortolone-21-valerate? Skin Pharmacol. 1993;6(4):276–281. 38. Medansky RS, Cuffie CA, Tanner DJ. Mometasone furoate 0.1%-salicylic acid 5% ointment twice daily versus fluocinonide 0.5% ointment twice daily in the management of patients with psoriasis. Clin Ther. 1997;19(4):701–709. 39. Reedy BL. A topical salicylate gel in the treatment of oral aphthous ulceration. Practitioner. 1970;204(224):846–850. 40. Goldsmith LA. Salicylic acid. Int J Dermatol. 1979;18(1): 32–36. 41. Kligman D, Kligman AM. Salicylic acid as a peeling agent for the treatment of acne. Cosmet Derm. 1997;10:44–47. 42. Kligman D, Kligman AM. Salicylic acid peels for the treatment of photoaging. Dermatol Surg. 1998;24(3):325–328. 43. Swinehart JM. Salicylic acid ointment peeling of the hands and forearms: effective nonsurgical removal of pigmented lesions and actinic damage. J Dermatol Surg Oncol. 1992;18(6): 495–498. 44. Freedburg IM, Baden HP. Metabolic response to exfoliation. J Invest Dermatol. 1962;38:277–284. 45. Kligman AM. A comparative evaluation of a novel low-strength salicylic acid cream and glycolic acid products on human skin. Cosmet Derm. 1997;10(suppl 4):11–15. 46. Joshi SS, Boone SL, Alam M, et  al. Effectiveness, safety, and effect on quality of life of topical salicylic acid peels for treatment of postinflammatory hyperpigmentation in dark skin. Dermatol Surg. 2009;35(4):638–644; discussion 644. 616.e1

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68. Salter WT. A Textbook of Pharmacology. Philadelphia: WB Saunders; 1952:913. 69. Miller HE. Colloidal sulfur in dermatology. Arch Dermatol Syphilol. 1935;31:516–525. 70. Gupta AK, Nicol K. The use of sulfur in dermatology. J Drugs Dermatol. 2004;3(4):427–431. 71. Schmidt NF, Gans EH. Demodex and rosacea, III: Treatment of Demodex mites associated with inflammatory rosacea. Cosmet Derm. 2004;10:655–658. 72. Osol A, Pratt R, Gennaro AR. The United States Dispensatory. 27th ed. Philadelphia: JB Lippincott; 1973:1123–1124. Sulfur—Clinical Use 73. Hjorth N. Traditional topical treatment of acne. Acta Derm Venereol Suppl (Stockh). 1980;89:53–56. 74. Blom I, Hornmark AM. Topical treatment with sulfur 10 per cent for rosacea. Acta Derm Venereol. 1984;64(4):358–359. 75. Bamford JT. Treatment of tinea versicolor with sulfur salicylic shampoo. J Am Acad Dermatol. 1983;8(2):211–213. 76. Bendl BJ. Perioral dermatitis: etiology and treatment. Cutis. 1976;17(5):903–908. 77. Hjorth N, Osmundsen P, Rook AJ, Wilkinson DS, Marks R. Perioral dermatitis. Br J Dermatol. 1968;80(5):307–313. 78. Ayres Jr S, Ayres 3rd S. Demodectic eruptions (demodicidosis) in the human. Arch Dermatol. 1961;83:816–827. 79. Thomas III JR, Daniel Su WP. The treatment of plane warts. Arch Dermatol. 1982;118:626. 80. Sheard C. Treatment of Skin Diseases: A Manual. Chicago: Year Book; 1978:21–22. 81. Mills Jr OH, Kligman AM. Is sulphur helpful or harmful in acne vulgaris? Br J Dermatol. 1972;86(6):620–627. 82. Strauss JS, Goldman PH, Nacht S, Gans EH. A re-examination of the potential comedogenicity of sulfur. Arch Dermatol. 1978;114(9):1340–1342. 83. Olansky S. Re-evaluation of sulfacetamide as a topical agent in the treatment of pustular acne. Cutis. 1967;3:611–614. 84. Olansky S. Old drug—in a new system—revisited. Cutis. 1977;19(6):852–854. 85. van Zuuren EJ, Fedorowicz Z, Carter B, van der Linden MM, Charland L. Interventions for rosacea. Cochrane Database Syst Rev. 2015;4:CD003262. 86. Strong M, Johnstone P. Interventions for treating scabies. Cochrane Database Syst Rev. 2007;3:CD000320. Sulfur—Adverse Effects 87. Rasmussen JR. Percutaneous absorption in children. In: Dobson RL, ed. Year Book of Dermatology. Chicago: Year Book; 1979:15–38. 88. Wilkinson DS. Sulphur sensitivity. Contact Dermatitis. 1975; 1(1):58. 89. Schneider HG. [Sulfur allergy]. Hautarzt. 1978;29(6):340– 342. 90. Williamson T, Kamalakar R, Ogbonnaya A, Zagadailov EA, Eaddy M, Kreilick C. Rate of adverse events and healthcare costs associated with the topical treatment of rosacea. Am Health Drug Benefits. 2017;10(3):113–119. Tar—History and Pharmacology 91. Kinmont PD. Tar and the skin. Practitioner. 1957;179(1073): 598–601. 92. Goeckerman WH. Treatment of psoriasis. Northwest Med. 1925;24:229. 93. Lin AN, Moses K. Tar revisited. Int J Dermatol. 1985;24(4): 216–218. 94. Lavker RM, Grove GL, Kligman AM. The atrophogenic effect of crude coal tar on human epidermis. Br J Dermatol. 1981;105(1):77–82.

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95. Lowe NJ, Breeding J, Wortzman MS. The pharmacological variability of crude coal tar. Br J Dermatol. 1982;107(4):475–479. 96. Walter JF, Stoughton RB, DeQuoy PR. Suppression of epidermal proliferation by ultraviolet light, coal tar and anthralin. Br J Dermatol. 1978;99(1):89–96. 97. Gloor M, Dressel M, Schnyder UW. The effect of coal tar distillate, cadmium sulfide, ichthyol sodium and omadine MDS on the epidermis of the guinea pig. Dermatologica. 1978;156(4):238–243. 98. Stoughton RB, DeQuoy PR, Walter JF. Crude coal tar plus near ultraviolet light suppresses DNA synthesis in the epidermis. Arch Dermatol. 1978;114(1):43–45. 99. Czarnetzki BM. Inhibitory effects of shale oils (Ichthyols) on the secretion of chemotactic leukotrienes from human leukocytes and on leukocyte migration. J Invest Dermatol. 1986;87(6):694–697. 100. Kownatzki E, Kapp A, Uhrich S. Inhibitory effect of sulfonated shale oils (ammonium bituminosulfate) on the stimulation of neutrophilic granulocytes by the chemotactic tripeptide f-MetLeu-Phe. Arch Dermatol Res. 1986;278(3):190–193. Tar—Clinical Use 101. Chan CS, Van Voorhees AS, Lebwohl MG, et al. Treatment of severe scalp psoriasis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2009;60(6): 962–971. 102. Listemann H, Scholermann A, Meigel W. [Antifungal activity of sulfonated shale oils.]. Arzneimittelforschung. 1993;43(7): 784–788. Tar—Possible Carcinogenicity 103. US Food and Drug Administration. Final Rule: Dandruff, seborrheic dermatitis and psoriasis drug products for over-thecounter human use. Federal Register. 1991;56:63554–63569. 104. Yamagiwa K, Ichikawa K. Experimental study of the pathogenesis of carcinoma. CA Cancer J Clin. 1977;27(3):174–181. 105. Jemec GBE, Øterlind A. Cancer in patients treated with coal tar: a long-term follow-up study. J Eur Acad Dermatol Venereol. 1994;3(2):153–156. 106. Pittelkow MR, Perry HO, Muller SA, Maughan WZ, O’Brien PC. Skin cancer in patients with psoriasis treated with coal tar. Arch Dermatol. 1981;117(8):465–468. 107. Jones SK, Mackie RM, Hole DJ, Gillis CR. Further evidence of the safety of tar in management of psoriasis. Br J Dermatol. 1985;113(1):97–101. 108. Maughan WZ, Muller SA, Perry HO, Pittelkow MR, O’Brien PC. Incidence of skin cancers in patients with atopic dermatitis treated with coal tar. J Am Acad Dermatol. 1980;3(6): 612–615. 109. Alexander JO, Macrosson KI. Squamous epithelioma probably due to tar ointment in a case with psoriasis. Br Med J. 1954;2(4896):1089. 110. Rasmussen JE. The crudeness of coal tar. Prog Dermatol. 1978;12:23–29. 111. Rook AJ, Gresham GA, Davis RA. Squamous epithelioma possibly induced by therapeutic application of tar. Br J Cancer. 1956;10(1):17–23. 112. Stern R, Zierler S, Parrish JA. Skin carcinoma in patient with psoriasis treated with topical tar and artificial ultraviolet radiation. Lancet. 1980;1(8171):732–735. 113. Fiala Z, Borska L, Pastorkova A, et al. Genotoxic effect of geokerman regimen of psoriasis. Arch Dermatol Res. 2006;298(5): 243–251. 114. Paghdal KV, Schwartz RA. Topical tar: back to the future. J Am Acad Dermatol. 2009;61(2):294–302. 115. Lowe FC. Squamous cell carcinoma of the scrotum. J Urol. 1983;130(3):423–427.

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116. McGarry GW, Robertson JR. Scrotal carcinoma following prolonged use of tar ointment. Br J Urol. 1989;63(2):211. 117. Andrews PE, Farrow GM, Oesterling JE. Squamous cell carcinoma of the scrotum: long-term follow up of 14 patients. J Urol. 1991;146(5):1299–1304. 118. Moy LS, Chalet M, Lowe NJ. Scrotal squamous cell carcinoma in a psoriatic patient treated with coal tar. J Am Acad Dermatol. 1986;14(3):518–519. 119. Schmid MH, Korting HC. Coal tar, pine tar and sulfonated shale oil preparations: comparative activity, efficacy and safety. Dermatology. 1996;193(1):1–5. Tar—Other Adverse Effects 120. Kaidbey KH, Kligman AM. Clinical and histological study of coal tar phototoxicity in humans. Arch Dermatol. 1977;113(5):592–595. 121. Gonçalo S, Sousa I, Moreno A. Contact dermatitis to coal tar. Contact Dermatitis. 1984;10(1):57–58. 122. Rietschel RL, Fowler JF, eds. Fisher’s Contact Dermatitis. 4th ed. Baltimore: Williams and Wilkins; 1995:153. 123. Rosyanto ID, van der Akker TW, van Joost TW. Wood tar allergy, cross-sensitization and coal tar. Contact Dermatitis. 1990;22(2):95–98. Urea—History and Pharmacology 124. Wohler F. On the artificial production of urea. Annalen der Physik und Chemie. 1828;12:88. 125. Port M, Sanicola KF. Nonsurgical removal of dystrophic nails utilizing urea ointment occlusion. J Am Podiatry Assoc. 1980;70(10):521–523. 126. Swanbeck G. The effect of urea on the skin with special reference to the treatment of ichthyosis. In: Marks R, Dykes PJ, eds. The Ichthyoses. Proc. 2nd Ann Clin Oriented Symp Eur Soc Dermatol. Cardiff. Lancaster: Technical Press; 1978:163–166. 1977. 127. Alexander MD, Haslewood ES, Haslewood GA, Watts DC, Watts RL. Osmotic control and urea biosynthesis in selachians. Comp Biochem Physiol. 1968;26(3):971–978. 128. Ashton H, Frenk E, Stevenson CJ. Therapeutics 13. Urea as a topical agent. Br J Dermatol. 1971;84(2):194–196. 129. Hellgren L, Larsson K. On the effect of urea on human epidermis. Dermatologica. 1974;149(5):289–293. 130. Swanbeck G. Urea in the treatment of dry skin. Acta Derm Venereol Suppl (Stockh). 1992;177:7–8. 131. Loden M. Urea-containing moisturizers influence barrier properties of normal skin. Arch Dermatol Res. 1996;288(2):103–107. 132. Feldman RJ, Maibach H. Percutaneous penetration of hydrocortisone with urea. Arch Dermatol. 1974;109(1):58–59. 133. Pinner TA, Jones RH, Bandisode MS. Study of efficacy of urea compound versus emollient cream in avulsive therapy of dystrophic nails. Cutis. 1990;46(2):156–157. 134. Grice K, Sattar H, Baker H. Urea and retinoic acid in ichthyosis and their effect on transepidermal water loss and water holding capacity of stratum corneum. Acta Derm Venereol. 1973;53(2):114–118. Urea—Clinical Use and Adverse Effects 135. Banerjee PK, Choudhury AK, Panja SK. Topical urea in dermatology. Indian J Dermatol. 1990;35(1):17–24. 136. van Zuuren EJ, Fedorowicz Z, Christensen R, Lavrijsen APM, Arents BWM. Emollients and moisturisers for eczema. Cochrane Database Syst Rev. 2017;2:CD012119. 137. Nasrollahi SA, Ayatollahi A, Yazdanparast T, et al. Comparison of linoleic acid-containing water-in-oil emulsion with urea-containing water-in-oil emulsion in the treatment of atopic dermatitis: a randomized clinical trial. Clin Cosmet Investig Dermatol. 2018;5(11):21–28.

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56 Irritants and Allergens: When to Suspect Topical Therapeutic Agents MICHAEL SHEEHAN

QUESTIONS Q56.1 What types of reactions are included under the term ‘contact dermatitis’? (Pg. 617) Q56.2 What is dermatitis medicamentosa? (Pg. 618)

Q56.6 What is the name of the allergen found in ophthalmic products and frequently reported as a cause of eyelid contact dermatitis? (Pg. 619)

Q56.3 What are some clues that help suggest the presence of contact dermatitis? (Pg. 618)

Q56.7 What allergen is thought to be the most common cause of photoallergic contact dermatitis? (Pg. 620)

Q56.4 Of the body regions covered in this chapter, which is the least likely to be affected by contact dermatitis? (Pg. 618)

Q56.8 Which class of corticosteroids is considered the most ‘hypoallergenic’? (Pg. 621)

Q56.5 What are some of the reasons for the frequency of contact dermatitis affecting the eyelids? (Pg. 619)

Q56.9 What allergen is frequently found in over-the-counter products marketed for anogenital use? (Pg. 622) Q56.10 What is the difference between cross-reaction and coreaction? (Pg. 622)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R ACD Allergic contact dermatitis ACDS American Contact Dermatitis Society BHA Butylhydroxyanisole BHT Butylhydroxytoluene ICD Irritant contact dermatitis NACDG North American Contact Dermatitis Group OTC Over the counter

Introduction The subject of contact dermatitis tends to polarize dermatologists into one of two camps. There are those who seem to live for the mere suggestion of patch-test placement whereas others cringe at the thought of it. It is the author’s opinion that the answer lies primarily in how contact dermatitis is learned. Many practitioners do not enjoy the subject of contact dermatitis because it is often viewed as a subject requiring memorization of hundreds of chemicals with little clinical utility. This chapter will present somewhat of a paradigm shift with regard to the approach to managing contact

PABA Para-aminobenzoic acid PG Propylene glycol PPD Paraphenylenediamine ROAT Repeat open application test SPF Sun protection factor TRUE Thin-layer rapid use epicutaneous test

dermatitis. The focus will be to de-emphasize rote memorization of contact allergens, emphasizing instead the core knowledge that can be broadly applied by dermatologists to various clinical scenarios.

Contact Dermatitis: The Concept It has been reported that 6% to 10% of all dermatology visits are as a result of contact dermatitis.1 Q56.1 One of the core concepts is that the term contact dermatitis is broad and is used to include allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), and the much less common contact urticaria. We will only discuss ACD and ICD. Within these subgroups almost any 617

618

PA RT X

Miscellaneous Topical Drugs

morphologic reaction on the skin is possible. However, eczematous reactions are most common—either acute eczematous eruptions (such as poison ivy) or chronic eczematous eruptions such as typical cases of chronic hand dermatitis. The general rule of thumb is that of all cases of contact dermatitis, 80% are irritant and 20% are allergic in nature.2 Q56.2 The term contact dermatitis medicamentosa is used when the allergen source is found to be a medicament (something used to treat, prevent, or alleviate the symptoms of disease).

Allergic Contact Dermatitis ACD is a classic type IV delayed hypersensitivity reaction with a resultant inflammatory response. ACD is both patient and allergen specific. This means that a specific patient with an intact and functioning immune system exposed to a specific allergen are both required. The term sensitizer is used in the world of contact dermatitis to refer to potential allergens capable of inducing type IV hypersensitivity in the skin. The terms ‘sensitizer’ and ‘allergen’ are often used interchangeably.

Irritant Contact Dermatitis ICD is the normal reaction of skin to a noxious stimulus. It involves a nonspecific inflammatory response. Virtually all patients will react to a given substance if the noxious threshold for that substance is reached. The noxious threshold is a function of three factors: (1) the innate irritant properties of the substance, (2) the exposure level—determined by concentration, frequency, and duration of exposure, and (3) the degree of penetration through the stratum corneum, which is affected both by the health of the stratum corneum and the degree of occlusion. ICD does not require specific antigen sensitization.

When to Suspect Contact Dermatitis Q56.3 Contact dermatitis should be suspected in any pruritic or painful cutaneous eruption that is refractory to conventional therapy. Although symptomatology is not specific, ACD tends to be associated with more pruritus and ICD is more likely to be reported as painful or uncomfortable. A thorough history coupled with a high index of suspicion is required in refractory, worsening, or intermittent flaring cases of dermatitis affecting any body site. Certain anatomic sites have a high incidence of contact dermatitis and should be considered to indicate a relatively high yield for patch-testing. Such sites include eyelids, lips, perioral area, neck, axilla, hands, feet, anogenital region, and lower legs. Contact dermatitis is much less likely to occur exclusively on the trunk, proximal extremities, and scalp. These latter distributions should reduce the suspicion of contact dermatitis and increase the suspicion of an endogenous dermatitis.

Regional Approach It is both more practical and more efficacious to learn contact dermatitis in a regional manner. Although any medicament may cause contact dermatitis medicamentosa at any body site where applied, this chapter will highlight the medicaments that are likely the etiology in certain regions of the body. Empirical Recommendations. For each area, the content will also include empirical recommendations for the initial

TABLE Topical Minoxidil Products 56.1

Product

Active Ingredient

Other Ingredients

Rite Aid

Minoxidil 5%

Propylene glycol, alcohol, water.

DS Laboratories Spectral

Minoxidil 5%

Propylene glycol, alcohol, water.

Rogaine Extra Strength Foam

Minoxidil 5%

Butylated hydroxytoluene, cetearyl alcohol, polysorbate 60, stearyl alcohol. Propylene glycol free.

management of suspected contact dermatitis until patch-testing can be performed or in cases in which patch-testing is unavailable. Patch-testing should routinely be performed in cases of suspected contact dermatitis if possible, and subsequent therapeutic choices should be guided by the results. Throughout this chapter the term hypoallergenic will be applied to medicaments that are of low allergenicity and unlikely to be implicated in ACD. These products are also typically of low irritant potential. Scalp. Q56.4 Practically speaking, contact dermatitis infrequently occurs on the scalp alone. This region is typically refractory to both ICD and ACD. Even in cases of ACD to paraphenylenediamine (PPD), a robust allergen found in dark hair dyes, the scalp is often spared or minimally involved, whereas there is exuberant dermatitis in a rinse-off pattern involving the hair margins, face (commonly eyelids), and neck. Of the relatively rare cases of ACD involving the scalp, haircoloring products appear to be the most important allergen source.3 Among the frequently prescribed topical agents in dermatology, minoxidil may be the most common agent to result in isolated scalp contact dermatitis. ICD is the most common result of topical minoxidil exposure, although there are case reports of ACD, photo ACD, pigmented contact dermatitis, and pustular ACD.4 It is important to keep in mind that contact dermatitis can be to either the active ingredient or to additives such as preservatives, solvents and emulsifiers, fragrances, or emollients. In the case of minoxidil, propylene glycol (PG) is a frequently used additive. PG is also very common in many prescription therapeutics, including foams, creams, gels, ointments, solutions, and topical antibacterials. In 2018, PG was selected as the American Contact Dermatitis Society’s (ACDS) Allergen of the Year. The reason for its selection was to highlight the controversies and evolving understanding of this potential allergen and irritant. Despite being nearly ubiquitous in topical and systemic products, allergy to PG appears uncommon with a reported prevalence ranging from 0.8% to 3.5%.5 One of the controversies surrounding PG is which concentration should be used for patch-testing. Initially PG was patch-tested at a concentration of 10%, which the North American Contact Dermatitis Group (NACDG) increased to 30% in 1996 and then to 100% in 2013, and which is now the recommended screening patch-test concentration according to the NACDG.5 Table 56.1 illustrates the vehicle ingredients found in some common over-the-counter (OTC) minoxidil scalp products.

CHAPTER 56

Irritants and Allergens: When to Suspect Topical Therapeutic Agents

TABLE Minimally Allergenic or Hypoallergenic Scalp 56.2 Products

TABLE Minimally Allergenic or Hypoallergenic 56.3 Prescription Topical Agents

Product

Common Allergens

Product

Loprox shampoo

None

Acne

Clobex shampoo

Coccamidopropyl betaine

Acanya gel

Propylene glycol

DHS tar shampoo (fragrance free)

None

Atralin gel

Parabens, BHT

Free and Clear shampoo

None

Benzaclin gel

None

RID Lice Removal shampoo

Fragrance

Differin gel (0.1%, 0.3%)

Propylene glycol, parabens

California Baby Supersensitive Shampoo & Bodywash

Parabens

Differin cream

Parabens

Duac gel

None

Neutrogena T/Sal shampoo

Cocamidopropyl betaine

Retin-A Micro gel (0.1%, 0.04%)

Propylene glycol, BHT

Tazorac gel

BHA, BHT

Tazorac cream

None

‘Hypoallergenic’ scalp products can be used empirically in the setting of a scalp dermatitis. Table 56.2 highlights some of the more useful scalp products that are minimally irritant or are hypoallergenic. Face. There are many cosmetic products in use that can cause ACD of the face, although a discussion of cosmetic products is beyond the scope of this chapter. However, a patient with a known allergy to commonly used inactive ingredients in prescription topical products used for acne, rosacea, seborrheic dermatitis, psoriasis, or actinic keratoses can present a therapeutic challenge. For these patients, Table 56.3 can help guide therapy. Eyelids. Products applied to the scalp commonly induce contact dermatitis of the eyelids. Q56.5 The predominant theory explaining this paradox is that the eyelid skin is thinner and more at risk for both ICD and ACD owing to greater percutaneous absorption. However, the greater incidence of eyelid dermatitis may have more to do with the functionality of the region than with the eyelid structure per se. The sphincter function of the orbicularis oculi leads to an accordion-like movement of the upper eyelid skin. This may allow potential allergens to become trapped and retained within the retracted folding skin when the eye is open, thereby predisposing to contact dermatitis. One study focusing on patch-test results of pure eyelid dermatitis found gold to be the most common, with fragrances (previously the most common allergen), preservatives, and surfactants (coccamidopropyl betaine) being noted as additional common etiologies.6,7 Topical medications still need to be considered as potential allergens with eyelid dermatitis, with 8% of relevant patch-test reactions being caused by topical antibacterial agents and 3% to active ingredients in topical corticosteroids (TCS). Q56.6 Other important sources commonly found in dermatologic therapies include benzalkonium chloride and benzyl alcohol. Benzalkonium chloride is a preservative that has frequently been implicated in eyelid dermatitis. It is important because it is found in many ophthalmic solutions.8 Benzyl alcohol is a preservative, solvent, and fragrance which is found in many topical medications. It is a naturally occurring constituent of Myroxylon pereirae (Balsam of Peru), jasmine, and ylang oil and has been reported in association with fragranceinduced eyelid dermatitis.8 OTC hydrocortisone products (0.5% and 1.0% strengths) commonly used to treat eyelid dermatitis have been listed as the 17th most common cause of ACD of the eyelids, interestingly with a similar incidence to tosylamide resins found in nail polish.

619

Common Allergens

Rosacea Finacea gel

Propylene glycol

Metrogel

Parabens, propylene glycol

Actinic Keratosis Solaraze gel

None

Zyclara cream

Parabens

Efudex cream

Propylene glycol, parabens

Seborrheic Dermatitis Topical corticosteroids

See Box 56.1

Promiseb cream

Propyl gallate

Tersi foam

Parabens, propylene glycol

Xolegel

BHT, propylene glycol

Psoriasis Topical corticosteroids

See Box 56.1

Dovonex cream

Diazolidinyl urea

Taclonex ointment

None

Vectical ointment

None

BHA, Butylhydroxyanisole; BHT, butylhydroxytoluene.

A clinical pearl that should lead to an increased suspicion of ACD of the eyelids is asymmetric eyelid involvement. A predominance of the lower eyelids with a ‘run-off or drip’ pattern should raise suspicion of ophthalmic solutions. Isolated asymmetric upper eyelid dermatitis is a clue to an allergen spread from the hand, such as hand sanitizer, hand soap, or hand moisturizer. Empiric recommendations when ACD is a suspected cause of eyelid dermatitis are that (1) one of the shampoos listed in Table 56.2 is used; (2) a facial cleanser from Table 56.4 is used; (3) a topical anti-inflammatory product from Box 56.1 is used; (4) a hand soap from Table 56.4 is used; and (5) a hypoallergenic hand moisturizer such as Eucerin Plus Intensive Repair Hand Crème or Neutrogena Norwegian Formula Hand Cream Fragrance Free is used. Lips and Perioral. In up to 25% of patients with recalcitrant cheilitis possibly caused by ACD, topical medicaments are

620

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Miscellaneous Topical Drugs

TABLE Minimally Allergenic or Hypoallergenic Facial 56.4 and Hand Cleansers

Product

Common Allergens

Dove Beauty Bar, Sensitive Skin, Unscented

Cocamidopropyl betaine

California Baby Supersensitive Shampoo & Bodywash

Parabens

Aveeno Moisturizing Bar for Dry Skin

None

Aquanil Cleanser

None

Albolene Moisturizing Cleanser

None

Tom’s of Maine Natural Moisturizing Bodywash Unscented

None

• BOX 56.1 Topical Products Recommended for

Empiric Use in Settings of Suspected Allergy To Topical Corticosteroids Nonallergenic Active Ingredient, Nonallergenic Vehicle Topicort ointment (desoximetasone 0.25% ointment, Taro Pharmaceuticals) Topicort gel (desoximetasone 0.5% gel, Taro Pharmaceuticals) Protopic ointment (tacrolimus 0.1%, 0.03% ointment, Astellas Pharma)

Nonallergenic Vehicle, Potentially Allergenic Active Ingredient Ointments Locoid ointment (hydrocortisone butyrate 0.1% ointment, Ferndale Labs) Generic triamcinolone 0.1% ointment Generic desonide 0.05% ointment

Liquids Locoid lotion (hydrocortisone butyrate 0.1% lotion, Ferndale Labs) Beta-Val lotion (betamethasone valerate 0.1% lotion, Teva Pharmaceuticals) Embeline lotion (clobetasol propionate 0.05% lotion, Coria Labs) Cormax lotion (clobetasol propionate 0.05% lotion, Watson Labs) Generic clobetasol 0.05% lotion Generic betamethasone dipropionate 0.05% lotion

Nonallergenic Corticosteroids, Potentially Allergenic Vehicle Cloderm cream (clocortolone 0.1% cream, Coria Labs); contains parabens

a significant cause.9 Data published by NACDG from 2001 to 2004 showed that medicaments and oral hygiene products were the third most common allergen source for isolated allergic contact cheilitis.10 Among the topical medicaments, neomycin, bacitracin, budesonide and tetracaine were the most commonly reported allergens. Empiric recommendations to patients when ACD is a suspected cause of lip/perioral dermatitis are that (1) only petroleum jelly or Vaniply ointment is used as a lip moisturizer; (2) a topical anti-inflammatory agent from Box 56.1 is used; (3) a toothpaste without typical flavoring agents is used, such as Tom’s of Maine Children’s Fluoride-Free Silly-Strawberry Toothpaste or Cleure Toothpaste for Sensitive Teeth with Baking Soda and Xylitol. Neck. Dermatitis of the neck should immediately bring to mind a differential diagnosis that includes rinse-off pattern contact dermatitis if the lateral neck is exclusively involved and a photocontact/photosensitive (ultraviolet [UV]-driven) dermatitis

if additional photodistributed areas are involved. A photodistribution can easily be mistaken for an airborne distribution and vice versa. They can be differentiated in that in a photodistributed pattern there is typically sparing under the chin and behind the earlobes. This also helps differentiate a rinse-off pattern, which frequently involves these sites. True photoallergic contact dermatitis is rare and a definitive diagnosis can only be made through photopatch testing.11 In cases of photopatch test-proven photoallergic contact dermatitis, chemical sunscreen agents are easily the most common perpetrators. Historically, the para-aminobenzoic acid (PABA) derivatives were blamed. It is rare to find PABA in sunscreens today, and the PABA ester padimate O and octyl dimethyl PABA are the only PABArelated products approved for use in the United States. These ester derivatives of PABA have rarely been reported to cause allergic and photoallergic contact dermatitis.12 Q56.7 The benzophenone derivatives have been the most frequently reported cause of sunscreen contact dermatitis and photocontact dermatitis since the 1980s. Benzophenone-3 (oxybenzone) is the most commonly implicated benzophenone derivative both of the above. Benzophenones were recognized as the allergen of the year in 2014 by the ACDS to raise awareness of the potential for allergy and photoallergy to this class of chemicals which have become ubiquitous.12 Empiric recommendations for patients with suspected ACD of the neck include to (1) use sunscreen that contains only physical blockers (titanium dioxide and zinc oxide) as the active ingredients, such as Vanicream sun protection factor (SPF) 30, Vanicream SPF 60, Blue Lizard Sensitive, or California Baby products, and (2) use a low allergenicity shampoo from Table 56.2. Hands. Dermatitis of the hands is common and the differential diagnosis can be lengthy. It is useful to consider two broad groups: (1) endogenous and (2) exogenous causes. Atopic dermatitis, chronic vesicular hand dermatitis (dyshidrosis, pompholyx), and psoriasiform dermatitis are among the major endogenous etiologies to consider in hand dermatitis. Both ICD and ACD fall under the exogenous causes of hand dermatitis. This division is somewhat artificial, given that there is often significant overlap. Topical contactants are more likely to result in the typical eczematous contact dermatitis. A cross-sectional analysis of 22,025 patients patch-tested between 1994 and 2004 by the NACDG showed that in patients with isolated hand dermatitis and positive patch-test reactions, the 10 most commonly positive allergens fell into four categories: (1) cosmetic ingredients (preservatives and fragrances), (2) metals, (3) rubber gloves, and (4) medicaments. One-third of the patients with hand dermatitis and positive patch tests also had relevant identifiable irritants, and in 50% of patients with isolated hand dermatitis the causes were deemed solely irritant in nature.13 PG is commonly found in many topical medicaments. As noted previously, it is a potential cause of both ICD and ACD. It was first used in pharmaceutical preparations in 1932 as a solvent and vehicle for bismuth to treat syphilis.14 Currently, PG is virtually ubiquitous, as illustrated by the fact that it is the most common allergen in (TCS). It is particularly common in branded ointments.15 The treatment for chronic hand dermatitis should be multifactorial and often involves the use of (TCS). There can be several reasons for treatment failure. As previously mentioned, the vehicle used can lead to either ICD or ACD, with PG being the most common offender. Sorbitan sesquioleate, isothiazolinones, lanolin, and formaldehyde-releasing preservatives are other common allergens found in TCS.15

CHAPTER 56

Irritants and Allergens: When to Suspect Topical Therapeutic Agents

621

TABLE Corticosteroid Classes Based On Cross-Reaction Potential 56.5

Class A

Class B

Class C

Class D1

Class D2

Patch-Test Screening Agent Tixocortol-21-pivalate

Budesonide

Desoximetasone

Hydroxycortisone-17butyrate

Commonly Encountered Corticosteroid Class Members Topical hydrocortisone

Amcinonide

Clocortolone pivalate

Hydrocortisone acetate

Desonide Fluocinolone acetonide

Desoximetasone

Systemic hydrocortisone Hydrocortisone butyrate

Methylprednisolone

Fluocinonide Halcinonide

Dexamethasone

Hydrocortisone valerate

Prednisolone

Triamcinolone acetonide

Prednisone

Triamcinolone diacetate

Less commonly, the active corticosteroid (CS) itself can cause ACD. CS can be subdivided into different structural classes, with agents in a particular class being more likely to cross-react with each other (see Table 56.3). ACD is most commonly seen to class A agents. This incidence may be explained by the relatively frequent OTC use of hydrocortisone, which belongs to this class. Class A CS allergy can now be screened for using the thin-layer rapid use epicutaneous (TRUE) test, which has tixocortal-21-pivalate. The TRUE test also now contains budesonide, which can be used to screen for allergic contact allergy to class B CS (Table 56.5). Q56.8 In general it is assumed that all agents in a class can cross-react. Furthermore, there can be significant cross-reaction between classes. Class A and B CS can both cross-react with class D2. Class C CS are rarely, if ever, the cause of ACD, and therefore are considered ‘hypoallergenic’. Box 56.1 highlights empiric hypoallergenic anti-inflammatory agents that can be tried in the case of suspected contact dermatitis to CS.15 Pearls regarding patch-testing to CS (including the TRUE test) are that CS patch-test reactions are often delayed and can be missed if only a 48-hour read is done, and that positive patch-test reactions have a high clinical relevance. Empiric recommendations when ACD of the hands is suspected are (1) the use of a topical anti-inflammatory agent from Box 56.1; (2) the use of a cleanser from Table 56.4; and (3) the use of a hypoallergenic hand moisturizer such as Eucerin Plus Intensive Repair Hand Crème or Neutrogena Norwegian Formula Hand Crème, Fragrance Free. Feet. The feet are interesting from a contact dermatitis perspective in that they have a very particular microenvironment as a result of being enclosed by footwear. A shoe dermatitis typically presents with dermatitis located at points of shoe contact (dorsal feet and toes). Other less recognized causes of ACD or ICD can be considered victims of this specific enclosed microenvironment— specifically, medicament allergens retained in shoes after application of the medicament to the feet.

Alclometasone dipropionate Betamethasone dipropionate Betamethasone valerate Clobetasone butyrate Fluticasone propionate Mometasone furoate

Prednicarbate

Topical products commonly can be leached into socks and the inner aspect of shoes. Because shoes are not routinely washed, the allergen is retained for long periods and potential exposure time is prolonged. The combination of retained allergens in both socks and shoes, friction, and moisture leads to an excellent environment for ACD. Topical medicaments are a leading cause of isolated foot dermatitis, with topical antibacterial agents being the most common allergens.16 Iatrogenic ACD of the feet can be the result of topical antibacterial agents (neomycin and bacitracin), topical antifungals, or TCS (vehicles or active ingredients). Topical antifungals are like CS in that ACD is more likely to result from the vehicle ingredients. In the case of allergy to the active ingredient a simple rule can help empirically choose another product that is unlikely to cross-react. Among the imidazole antifungals, econazole and miconazole are structurally similar and frequently cross-react, whereas ketoconazole and clotrimazole are structurally less similar. Empiric recommendations for suspected ACD of the feet are (1) that hyperhidrosis is addressed if possible; (2) the use of a topical anti-inflammatory agent from Box 56.1; (3) the complete avoidance of wearing all shoes and socks that were possibly contaminated with topical products, such as antifungals, antibacterials, or TCS for at least 6 weeks; and (4) that agents from Box 56.2 are used if topical antibacterials or antifungals are necessary. Anogenital. The anogenital region is a common site for dermatitis medicamentosa. This predisposition is multifactorial theoretically as a result of (1) the intertriginous and mucosal surfaces of the anogenital region having less of a stratum corneum barrier; (2) this anatomic region being a site of friction and sweating, both of which further diminish the natural barrier function; and (3) the skin folds leading to retained allergens and occlusion. These factors, combined with the fact that patients are likely to self-treat with multiple OTC products for various anogenital symptoms, creates the relatively high-risk situation for the development of contact dermatitis.

622

PA RT X

Miscellaneous Topical Drugs

• BOX 56.2 Hypoallergenic Topical Antibacterials and

Antifungals Antibacterial Mupirocin ointment

Antifungal Micatin cream Desenex liquid spray Lotrimin AF cream Lotrimin powder and powder spray Tinactin liquid spray and superabsorbent powder

As in all cases of contact dermatitis, it is important to first consider ICD. This is probably most critical in the setting of anogenital dermatitis. Margesson17 reviewed contact dermatitis of the vulva and the importance of irritants in this setting. Notable irritants used in dermatology are podophyllin, podofilox, soaps, wipes, and PG. Q56.9 The major suspects in anogenital ACD are topical anesthetics, antibacterial agents, TCS, antiseptics, and preservatives. Wet wipes are common irritants owing to their alcohol content, and allergenic caused by the preservatives and fragrances they commonly contain. Also, it is common for patients with anogenital dermatitis to have multiple sensitivities.9 Marren and colleagues18 reported that 39 of 135 patients with vulvar itch and discomfort were found to have relevant positive patch tests. The majority of these were related to medicaments, especially benzocaine found in many OTC products marketed for anogenital use. Muratore and coworkers19 reported a patient with penile dermatitis related to the benzocaine gel in his condoms for increased sexual performance. This case highlights the potential pitfall of dermatitis medicamentosa incognito, in which the medicament is hidden in a personal use product. Another pitfall is that patients with a primary anogenital dermatosis often develop a secondary ACD. For example, patients with lichen sclerosus have high rates of positive patch-test results.20 It is important to consider patch-testing in patients with an anogenital dermatosis who fail to respond to conventional therapies. ACD of the anogenital region should be the presumed diagnosis if there is both anogenital dermatitis and dermatitis of the fingers of one hand, as the hand is used to apply agents to the area or to clean the area with wipes. Empiric recommendations for suspected ACD of the anogenital region are (1) that the area is only cleaned with cleansers from Table 56.4; (2) to avoid all wipes; (3) to moisturize the area only with petroleum jelly; (4) to use a minimally or hypoallergenic topical therapeutic from Box 56.1; (5) to avoid all OTC or prescription products, especially those that contain benzocaine; and (6) to avoid wearing old/unwashed underwear, as these may be contaminated with the allergen. Stasis Dermatitis and Chronic Leg Ulcers. The setting of stasis dermatitis and chronic leg ulcers is a similarly high-risk scenario for the development of ACD. Patients often apply multiple OTC medicaments covering a spectrum of analgesics, antiinflammatory products, and antibacterial agents. There is also an innate predisposition to sensitization, given the decreased barrier

function seen in edematous/inflamed and ulcerated extremities. Q56.10 The quintessential example of ACD in the setting of stasis dermatitis and chronic leg ulcerations is topical antibacterials such as neomycin and bacitracin. Bacitracin was named NACDG contact allergen of the year in 2003, and neomycin in 2010.21,22 One important point to remember with respect to topical antibacterial agents is the concept of co-reaction. This is different from cross-reaction. In cross-reactions a patient is sensitized to a particular allergen. They can then develop a type IV hypersensitivity reaction if exposed to a structurally similar allergen. An example would be neomycin and gentamicin, which are structurally very similar. In contrast, co-reaction occurs when two potential allergens are frequently used together in a single medicament, thereby increasing the chance that a patient becomes sensitive to both. There is no requirement for structural similarity. The classic example is neomycin and bacitracin, which are commonly in the same products (‘triple antibiotics’). Clinical Pearls. Two important ‘clinical pearls’ are that (1) because antibiotic preparations are applied to already damaged skin, ACD from neomycin or bacitracin is not always easily recognized and (2) ACD often presents as the persistence, worsening of a pre-existing dermatitis or sudden ‘Id’ reaction. Several studies have highlighted the importance of topical medicaments in the setting of stasis dermatitis and chronic leg ulcers.23 Anaphylaxis is a rare but, potentially life-threatening effect of topical bacitracin.24 The risk of anaphylaxis is highest when bacitracin is applied to open wounds such as lower extremity ulcers. Empiric recommendations for suspected ACD in the setting of stasis dermatitis or chronic leg ulcers are that (1) only desoximetasone ointment is used as a topical therapeutic; (2) only petroleum jelly is used as a moisturizer on the area; and (3) if a topical antibacterial agent is needed, the use of dilute Dakin’s Solution (1 tablespoon of regular bleach in 32 oz of water) or topical mupirocin ointment should be strongly considered.

Final Thoughts Contact dermatitis medicamentosa can potentially cause a dermatitis anywhere on the body, acting either as an irritant or as a true allergen. Further complicating this issue, both the active ingredient and additives of the product need to be considered. Patch-testing is the gold standard by which the role of allergens should further be investigated. In this manner one can delineate the degree of true allergenicity versus irritancy. A repeat open application test (ROAT) is a ‘usage test’ that can also be employed in the clinical setting to test a potential culprit product for allergenicity. This requires the patient to apply the test substance twice daily to the antecubital area for 2 weeks, thereby recreating the actual exposure of the potential allergen. ACD is suspected when the acute dermatitic eruption persists for at least 7 to 10 days after cessation of the applications. For extended patch-testing, referral to a patch-test clinic is often extremely helpful.

Acknowledgment The author would like to acknowledge the contributions of Dr. Nico Mousdicas and Matthew J. Zirwas to the previous edition of this chapter.

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Irritants and Allergens: When to Suspect Topical Therapeutic Agents

Bibliography: Important Reviews and Chapters Contact dermatitis. Dermatol Clin. 2009;27(3). (Entire issue.). Gehrig KA, Warshaw EM. Allergic contact dermatitis to topical antibiotics: Epidemiology, responsible allergens, and management. J Am Acad Dermatol. 2008;58(1):1–21. Jacob SE, Steele T. Corticosteroid classes: a quick reference guide including patch test substances and cross-reactivity. J Am Acad Dermatol. 2006;54(4):723–727. Johansen JD, Aalto-Korte K, Agner T, et al. European Society of Contact Dermatitis guideline for diagnostic patch testing – recommendations on best practice. Contact Dermatitis. 2015;73(4):195–221. McGowan MA, Scheman A, Jacob SE. Propylene glycol in contact dermatitis: a systematic review. Dermatitis. 2018;29(1):6–12. Saary J, Qureshi R, Palda V, et al. A systematic review of contact dermatitis treatment and prevention. J Am Acad Dermatol. 2005;53(5): 845.e1–e13.

References* 1. Krob AH, Fleischer Jr AB, D’Agostino R, et al. Prevalence and relevance of contact dermatitis allergens: a meta-analysis of 15 years of published T.R.U.E. Test data. J Am Acad Dermatol. 2004;51:349–353. 2. Marks JG, Elsner P, DeLeo VA. Contact & Occupational Dermatology. St. Louis, MO: Mosby; 2002:4.

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3. Hillen U, Grabbe S, Uter W. Patch test results in patients with scalp dermatitis: analysis of data of the information network of departments of dermatology. Contact Dermatitis. 2007;56(2):87–93. 4. Rodriguez-Martin M, Saez-Rodriguez M, Carnerero-Rodriguez A, et al. Pustular allergic contact dermatitis from topical minoxidil 5%. J Eur Acad Dermatol Venereol. 2007;21(5):701–702. 5. Jacob S, Scheman A, McGowan M. Propylene glycol. Dermatitis. 2018;29(1):3–5. 6. Rietschel RL, Warshaw EM, Sasseville D, et al. Common contact allergens associated with eyelid dermatitis: data from the north american contact dermatitis group 2003–2004 study period. Dermatitis. 2007;18(2):78–81. 7. Amin KA, Belsito DV. The aetiology of eyelid dermatitis: a 10-year retrospective analysis. Contact Dermatitis. 2006;55(5):280–285. 8. Jacob SE, Stechschulte S. Eyelid dermatitis associated with balsam of Peru constituents: benzoic acid and benzyl alcohol. Contact Dermatitis. 2008;58(2):111–112. 9. Davis MD. Unusual patterns in contact dermatitis: medicaments. Dermatol Clin. 2009;27(3):289–297. 10. Zug K, Kornik R, Belsito DV, et al. Patch-testing North American lip dermatitis patients: data from the North American contact dermatitis group, 2001 to 2004. Dermatitis. 2008;19(4):202–208.

*Only a selection of references are printed here. All other references in the reference list are available online at www.expertconsult.com.

Web References 1. Krob AH, Fleischer Jr AB, D’Agostino R, et al. Prevalence and relevance of contact dermatitis allergens: a meta-analysis of 15 years of published T.R.U.E. Test data. J Am Acad Dermatol. 2004;51:349–353. 2. Marks JG, Elsner P, DeLeo VA. Contact & Occupational Dermatology. St. Louis, MO: Mosby; 2002:4. 3. Hillen U, Grabbe S, Uter W. Patch test results in patients with scalp dermatitis: analysis of data of the information network of departments of dermatology. Contact Dermatitis. 2007;56(2): 87–93. 4. Rodriguez-Martin M, Saez-Rodriguez M, Carnerero-Rodriguez A, et al. Pustular allergic contact dermatitis from topical minoxidil 5%. J Eur Acad Dermatol Venereol. 2007;21(5):701–702. 5. Jacob S, Scheman A, McGowan M. Propylene glycol. Dermatitis. 2018;29(1):3–5. 6. Rietschel RL, Warshaw EM, Sasseville D, et al. Common contact allergens associated with eyelid dermatitis: data from the north american contact dermatitis group 2003–2004 study period. Dermatitis. 2007;18(2):78–81. 7. Amin KA, Belsito DV. The aetiology of eyelid dermatitis: a 10-year retrospective analysis. Contact Dermatitis. 2006;55(5):280–285. 8. Jacob SE, Stechschulte S. Eyelid dermatitis associated with balsam of Peru constituents: benzoic acid and benzyl alcohol. Contact Dermatitis. 2008;58(2):111–112. 9. Davis MD. Unusual patterns in contact dermatitis: medicaments. Dermatol Clin. 2009;27(3):289–297. 10. Zug K, Kornik R, Belsito DV, et al. Patch-testing North American lip dermatitis patients: data from the north american contact dermatitis group, 2001 to 2004. Dermatitis. 2008;19(4): 202–208.

11. Shaw T, Simpson B, Wilson B, et al. True photoallergy to sunscreens is rare despite popular belief. Dermatitis. 2010;21(4):185–198. 12. Heurung A, Raju S, Warshaw E. Benzophenones. Dermatitis. 2014;25(1):3–10. 13. Warshaw EM, Ahmed RL, Belsito DV, et al. Contact dermatitis of the hands: cross-sectional analyses of North American contact dermatitis group data, 1994–2004. J Am Acad Dermatol. 2007;57(2):301–314. 14. Catanzaro JM, Smith Jr JG. Propylene glycol dermatitis. J Am Acad Dermatol. 2007;57(2):301–314. 15. Coloe J, Zirwas MJ. Allergens in corticosteroid vehicles. Dermatitis. 2008;19(1):38–42. 16. Shackelford KE, Belsito DV. The etiology of allergic-appearing foot dermatitis: A 5-year retrospective study. J Am Acad Dermatol. 2002;47(5):715–721. 17. Margesson LJ. Contact dermatitis of the vulva. Dermatol Ther. 2004;17(1):20–27. 18. Marren P, Wojnarowska F, Powell S. Allergic contact dermatitis and vulvar dermatoses. Br J Dermatol. 1992;126(1):52–56. 19. Muratore L, Calogiuri G, Foti C, et al. Contact allergy to benzocaine in a condom. Contact Dermatitis. 2008;59(3):173–174. 20. Utaş S, Ferahbaş A, Yildiz S. Patients with vulval pruritus: patch test results. Contact Dermatitis. 2008;58(5):296–298. 21. Sasseville D. Contact allergen of the year: neomycin. Dermatitis. 2010;21(1):3–7. 22. Sood A, Taylor J. Contact allergen of the year: bacitracin. Dermatitis. 2003;14(1):3–4. 23. Saap L, Fahim S, Arsenault E, et al. Contact sensitivity in patients with leg ulcerations: a North American study. Arch Dermatol. 2004;140(10):1241–1246. 24. Schechter JF, Wilkinson RD, Del Carpio J. Anaphylaxis following the use of bacitracin ointment. Arch Dermatol. 1984;120:909–911.

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57 Miscellaneous Topical Agents KATHERINE ROY AND SETH B. FORMAN

QUESTIONS Q57.1 What is the function of endogenous vitamin C, and by what mechanisms does topical vitamin C reportedly reduce clinical findings of photoaging? (Pg. 625) Q57.2 What are the clinical advantages of aluminum chloride used for hemostasis, compared with Monsel’s solution and electrocautery? (Pg. 627x2) Q57.3 How are aluminum chloride products typically used for treatment of hyperhidrosis? (Pg. 627) Q57.4 What are the most likely mechanisms by which topical minoxidil induces hair growth? (Pg. 627) Q57.5 Which products discussed in this chapter have literature reports to support off-label use for selected cases of alopecia areata? (Pg. 628)

Q57.6 What is the proposed mechanism of action for anthralin? (Pg. 629x2) Q57.7 What are the rationale and therapeutic guidelines for shortcontact anthralin therapy (SCAT) (Pg. 629x3) Q57.8 What is the most common adverse effect for topical brimonidine gel? (Pg. 629) Q57.9 What serious adverse effect has been reported for topical brimonidine gel for achieving hemostasis in the peri-operative setting? (Pg. 629) Q57.10 What other α-adrenergic receptor agonist has been shown to improve the persistent facial erythema from rosacea with once daily application? (Pg. 630)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R ATP Adenosine triphosphate CEFer Vitamin C, Vitamin E, ferulic acid OTC Over the counter PDL Pulsed-dye laser

SCAT Short-contact anthralin therapy UVA Ultraviolet A UVB Ultraviolet B VEGF Vascular endothelial growth factor

Introduction

is amplified by the media. Unfortunately, data concerning the clinical use of these topically applied agents in human subjects are scarce. The most recent supporting evidence, with theoretical clinical correlations, is discussed. The physiologic antioxidants are reviewed in greater detail below and in table form (Table 57.1), with plant antioxidants listed in table form only (Table 57.2). The topical antioxidants discussed in this section include ascorbic acid (vitamin C), vitamin E, selenium, and zinc. The greatest emphasis will be given to ascorbic acid and vitamin E.

This chapter on miscellaneous topical agents is divided into three sections: (1) topical antioxidants, (2) topical agents for hemostasis and hyperhidrosis, and (3) other topical agents (Box 57.1). Many of the topical therapeutics discussed in this chapter are available in over-the-counter (OTC) preparations; only a few of these medications require a prescription, namely bimatoprost, brimonidine, and anthralin. Oxymetazoline 1% cream is available by prescription, although the 0.05% nasal solution is available over the counter. Eskata is intended for in-office use only.

Topical Antioxidants The incorporation of antioxidants into topical formulations is a response to overwhelming demand from the lay public, which 624

Ascorbic Acid (Vitamin C) Pharmacology

A variety of commercially available preparations of topical vitamin C are available over the counter in varying concentrations, including products by Skinceuticals, Cellex-C International, and Revision, among others.

CHAPTER 57

Mechanism of Action. Q57.1 Ascorbic acid is a necessary cofactor for the enzymes prolyl hydroxylase and lysyl hydroxylase. These enzymes are used in the formation of a stable collagen molecule and the cross-linking of collagen, respectively. • BOX 57.1 Drugs Discussed in This Chapter Topical Antioxidants Ascorbic acid (vitamin C) Vitamin E Selenium Zinc (Plant antioxidants—Table 57.2)

Topical Agents for Hemostasis and Hyperhidrosis Aluminum chloride Ferric subsulfate (Silver nitrate—Table 57.3)

Miscellaneous Topical Agents

625

L-ascorbic acid is the predominant cutaneous antioxidant. It is theorized that topical ascorbic acid scavenges free oxygen radicals in the aqueous compartments, and in addition stimulates collagen synthesis. Alone, ascorbic acid does not absorb ultraviolet A (UVA) or ultraviolet B (UVB), but L-ascorbic acid in combination with α-tocopherol (vitamin E) has recently been shown to provide the skin with significant UVA and UVB protection. Vitamin C protects vitamin E from oxidation. Topical 15% L-ascorbic acid and 1% α-tocopherol provide a marked increase in photoprotectivity.1,2 Another issue is the bioavailability of topically applied vitamin C. The addition of tyrosine and zinc to vitamin C has been shown to provide more than 20 times the amount of ascorbic acid found in normal skin.3,4 The Cellex-C Advanced-C Serum contains resveratrol (a free radical scavenger extracted from mulberries and grapes) and L-ergothioneine (also a natural antioxidant) to further stabilize vitamin C. Clinical Use Dermatologic Uses Photoaging. Topical ascorbic acid is commonly used in the

Other Topical Agents Phytonadione (vitamin K1) Minoxidil Bimatoprost Capsaicin Anthralin Aloe vera Brimonidine Oxymetazoline Hydrogen peroxide

treatment of photoaged skin. Although few randomized controlled trials in humans have been carried out, limited data suggest it may improve the appearance of photodamaged skin.5 One randomized, double-blind, vehicle-controlled study showed improvement in fine wrinkling, tactile roughness, coarse rhytides, skin laxity, and yellowing. The greatest clinical improvement was noted for tactile roughness/texture and skin hydration.3

TABLE Physiologic Antioxidants 57.1

Antioxidant

Chemical Name

Mechanism of Action

Possible Uses

Vitamin C

L-ascorbic acid

Aqueous reductant, free radical scavenger

UVA/UVB protection, photoaging

Vitamin E

Tocopherola

Prevents lipid peroxidation

UVA/UVB protection, psoriasis

Selenium

L-selenomethionine

Cofactor for glutathione peroxidase and thioredoxin reductase

Photoprotection

Zinc

Zinc

Not well understood—may compete with harmful freeradical-producing Fe2+ and Cu+ in cellular reactions, and/or meteallothioninb

Photoprotection

aMost

active form is α-tocopherol. mechanism. UVA, Ultraviolet A; UVB, ultraviolet B. bTheoretical

TABLE Plant Antioxidants4 57.2

Antioxidant

Source

Mechanism of Action

Possible Uses

Silymarin

Extract of milk thistle plant (Silybum marianum)

Prevents lipid peroxidation, inhibits lipoprotein oxidation, scavenges reactive oxygen species

UVB photoprotection, anticarcinogenic

Genistein

Soybeans (soy isoflavones)

Inhibitor of tyrosine kinase, prevents lipid peroxidation, scavenges peroxyl radicals

UVA/UVB photoprotection, anti-carcinogenic

Green tea polyphenols

Camellia sinensis (tea)

Reduces lipid peroxidation, quenches free oxygen radicals

UVA/UVB photoprotection, antiangiogenic, anticarcinogenic

UVA, Ultraviolet A; UVB, ultraviolet B.

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In another small, randomized, split-face trial in 10 patients, a mixture of water- and lipid-soluble forms of vitamin C were found to significantly improve the appearance of photoaged skin. This included demonstrating increased collagen production on punch biopsy specimens.6 In a placebo-controlled trial, 3% vitamin C cream was found to improve the appearance of photoaging of the forearm skin of 33 women, which was correlated with microscopic findings of increased density of dermal papillae.7 Vitamin C has also been shown to inhibit melanogenesis induced by UVA,8 and has been used with some success both in topical and mesotherapy (injected) forms to improve periorbital dark circles,9,10 as well as in combination with other treatments for melasma.11 Photoprotection. Lin and associates12 elucidated the advantage of a combination of vitamin C and vitamin E for absorbing UVA and UVB radiation, over either topically applied vitamin alone. The study was performed on porcine models. These results and others are now reflected in the addition of both vitamin C and vitamin E in sunscreens, daily moisturizers, and other nonprescription skin care products.1,13 Investigation of vitamins C and E combined with ferulic acid (a plant-derived antioxidant) has further demonstrated both improved chemical stability and a doubled photoprotective ability.12 In another study of the above combination (abbreviated CEFer), UVB-exposed skin of treated patients demonstrated significant protection from induction of erythema, sunburn cells, and thymine dimer formation.3 Adverse Effects. Topical ascorbic acid adverse events (AE) are mild and typically resolve in the first 2 months of continuous therapy. These minor AE included stinging (55%), erythema (24%), and dry skin (1%).3 Therapeutic Guidelines. After cleansing areas that will be exposed to sunlight, vitamin C-containing compound (or combination product with vitamins C and E) is applied evenly over the skin surface. Sunscreens may be applied subsequently, ideally allowing 30 minutes or more between products to avoid significant dilution. Pregnancy Prescribing Status. Oral ascorbic acid (vitamin C) is pregnancy prescribing class C. There are no pregnancy guidelines for the topically applied formulations.

Vitamin E Pharmacology

There are eight molecular forms of vitamin E—four tocopherols and four tocotrienols. Of these eight molecular forms, α-tocopherol is the most physiologically active isomer, owing to the presence of a specific α-tocopherol transfer protein. The transfer protein selectively transfers α-tocopherol into lipoproteins.13 Mechanism of Action. Vitamin E is a free radical scavenger that prevents lipid peroxidation. It is the major lipid phase antioxidant in humans. Vitamin E is the main lipid-soluble antioxidant for the protection of cell membranes. Clinical Use Dermatologic Uses Photoprotection. Topical vitamin E has been effective in

reducing UV-induced erythema and edema in murine models. It has also been shown to reduce skin photoaging effects, skin cancer, and UV radiation-induced immunosuppression in animals. More specifically, α-tocopherol inhibits cyclopyrimidine dimer formation via the epidermal p53 tumor suppressor gene.13 The photoprotective combination of topically applied vitamin E with vitamin C was discussed in an earlier section.13

Adverse Effects. Overall, AE from vitamin E are quite uncommon.14 Vitamin E may inhibit clotting, and therefore it may be unwise to apply these products on an open, healing wound. There are no published data concerning the use of these products in pregnancy.

Selenium Selenium is an essential cofactor for glutathione peroxidase and thioredoxin reductase. The aforementioned enzymes are very important in cellular defense against oxidative stress. Topical L-selenomethionine has been shown to increase the minimal erythema dose of UV radiation in human subjects. Further studies on murine models illustrated protection against UVinduced erythema and skin cancer.13 The L-selenomethionine compound studied in the aforementioned trial is not yet commercially available. Several related products (without published data concerning their use) with L-selenomethionine include Vitastic Soothing Shave Gel and Perfect Day Vitamin and Mineral Formula.

Zinc The protective properties of topically applied zinc compounds are not yet fully understood. One possible mechanism is that zinc replaces harmful redox-active entities, including Fe2+ and Cu+. A second theory suggests that zinc induces the synthesis of metallothionein, a free radical scavenger which plays a role in heavy-metal detoxification.13,15 An experimental model in hamsters demonstrated an increase in metallothionein protein in skin treated with a topical erythromycin and zinc preparation (Zineryt).16 The topical application of zinc salts to murine models was shown to reduce UV-induced sunburn cell formation.13 In vitro studies with cultured human fibroblasts also demonstrate the protective effect of zinc on UVA induced DNA damage.17 In a small study of Iraqi patients with melasma, a 10% zinc sulfate lotion applied twice daily was found to produce a significant improvement in the condition. The authors attributed the efficacy to the photoprotective and antioxidant effects of zinc.18

Topical Agents for Hemostasis and Hyperhidrosis This section of the chapter includes discussion of two drugs: (1) aluminum chloride, and (2) ferric subsulfate (Monsel’s solution). The products are discussed in some detail because of the widespread use of these agents in dermatology. Silver nitrate, which is less commonly used in dermatology, is mentioned briefly in table format only (Table 57.3). Brimonidine gel is discussed later in this chapter with other topical agents, given its primary use for rosacea; it has also been used for perioperative hemostasis.

Aluminum Chloride Pharmacology

Aluminum chloride has the chemical formula AlCl3. This drug is available as a 20% solution in anhydrous ethyl alcohol (Drysol) and a 12% solution (Certain Dri pads and roll-on bottle). Mechanism of Action. Aluminum chloride reversibly inhibits eccrine gland secretion by obstructing the eccrine pores and

CHAPTER 57

TABLE Topical Hemostatic Agents5,10,12 57.3

Miscellaneous Topical Agents

N

Common Name

Chemical Name

Chemical Formula

Clinical Uses

Monsel’s solution

Ferric sulfate/ ferric subsulfate

Fe2(SO4)3

Hemostasis

Aluminum chloride

Aluminum chloride

AlCl3

Hemostasis, hyperhidrosis

Silver nitrate

Silver nitrate

AgNO3

Hemostasis, antimicrobial

N

627

NH2

N O NH2

inducing transient secretory cell atrophy. Aluminum creates a lowgrade generation of thrombin, which is followed by activation of the platelet-dependent clotting factor XI to XIa. Clinical Use Dermatologic Uses Hemostasis During Surgical Procedures. Aluminum chloride

20% is most often used for hemostasis after minor procedures such as shave biopsies or curettage. Q57.2 The advantage of aluminum chloride over Monsel’s solution is that it does not leave an iron residue that can persist in the dermis, essentially creating a tattoo. The advantage of aluminum chloride over electrocautery for hemostasis is that aluminum chloride does not cause as much scarring. In contrast, more pronounced bleeding during a procedure will typically require electrocautery for hemostasis. Hyperhidrosis. Aluminum chloride is useful for the treatment of palmar, plantar, and axillary hyperhidrosis.19 Aluminum chloride has also been reported to be useful in facial and scalp hyperhidrosis.20,21 Prevention of foot blisters caused by walking long distances in the heat, such as in hikers and military recruits, is an additional use for aluminum chloride.22,23 Adverse Effects. Uncommon minor reactions include irritant contact dermatitis, burning, or a prickling sensation.19 Significant caution should be given for use near the eye. Clinicians should be aware that aluminum chloride may be flammable if not allowed to dry completely before electrocautery (alternatively, rinse well with water).

• Fig. 57.1

Chemical structure of minoxidil.

Other hemostatic methods (aluminum chloride, electrocautery) are preferred over Monsel’s solution, which is uncommonly used in dermatology today.

Other Topical Agents The following topical drugs are discussed in this section: (1) phytonadione (vitamin K1), (2) minoxidil, (3) bimatoprost, (4) capsaicin, (5) anthralin, (6) aloe vera, the alpha adrenergic agonists (7) brimonidine and (8) oxymetazoline, and (9) hydrogen peroxide.

Phytonadione (Vitamin K1) Pharmacology

Topically applied vitamin K cream is commercially available in a variety of OTC formulations, generally in a 2% or 5% concentration. The precise mechanism of action for topically applied phytonadione is unknown. Oral vitamin K is used to treat bleeding diatheses in patients on warfarin anticoagulation through hepatic generation of ‘vitamin K-dependent’ clotting factors II, VII, IX, and X. Clinical Use

In trauma-induced purpura, the bruising cleared in 5 to 8 days in the treated bruises versus 11 to 13 days in the untreated bruises.26 The ability of topical vitamin K to reduce bruising and purpura in a postprocedural setting may be of special interest to the cosmetic practitioner. One trial of 22 patients receiving pulsed-dye laser (PDL) therapy demonstrated that although pretreatment with topical vitamin K did not prevent bruising, posttreatment use did speed resolution after bruises developed.27 Another recent trial of 20 patients revealed similar findings of faster resolution of laser-induced purpura,28 and suggested topical vitamin K1 use for prevention of bruising from injections and other cosmetic procedures. AE are negligible.

Therapeutic Guidelines for Treatment of Hyperhidrosis.

Q57.3 Recommendations regarding the frequency of applications for hyperhidrosis vary in the literature, ranging from daily to once weekly. Generally, it is believed that the lower-concentration solutions can be applied daily. Initially, the 20% solution can be used daily, and then tapered to thrice weekly or even once weekly as needed. The solution should be applied to completely dry skin.19

Ferric Subsulfate Ferric subsulfate (also known as Monsel’s solution) acts as a precipitating agent. The coagulated protein mechanically seals the small blood vessels. Ferric subsulfate has historically been used primarily for hemostasis during cutaneous procedures. Q57.2 The application of Monsel’s solution may result in hyperpigmentation and iatrogenic tattooing. Histopathologically, excision biopsies of an area chemically cauterized with Monsel’s solution may resemble malignant melanoma or an atypical fibroxanthoma.24,25

Minoxidil Pharmacology

Minoxidil (Rogaine) is available in 2% and 5% topical solutions and 5% foam. The 2% solution contains 60% alcohol. The 5% solution contains 30% alcohol (Fig. 57.1). Mechanism of Action. Q57.4 Minoxidil increases the duration of the anagen growth phase and gradually enlarges miniaturized hair follicles (vellus hairs) into mature terminal hairs.29 However, the precise biochemical mechanism by which minoxidil stimulates hair growth is uncertain. However, there is evidence regarding its effect on potassium channels. Minoxidil is an adenosine triphosphate (ATP)-sensitive potassium channel opener. The increase in ATP results in a release of adenosine. Vascular endothelial growth factor (VEGF), a proposed promoter of hair growth, is stimulated by adenosine signaling pathways. Also, prostaglandins are stimulated by minoxidil in the dermal papillae.

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Clinical Use US Food and Drug Administration-Approved Indications Male-Pattern Androgenetic Alopecia. The products (both concen-

trations) are indicated for use in male-pattern androgenetic alopecia of the vertex of the scalp. The drug usually preserves, if not reduces, the horizontal diameter of alopecia in the crown area.30 Studies show that in the first 4 months of treatment, vellus hair growth constitutes much of the total hair regrowth. Thereafter terminal hair growth becomes noticeable, and these terminal hairs may increase in number. Minoxidil is most efficacious in the treatment of androgenetic alopecia affecting the crown area up to 12 months. Therapy with minoxidil should be continued at the full twice-daily schedule indefinitely, because patients who go to a daily maintenance schedule beginning at 12 months may have decreased hair counts.31–33 The foam formulation may be more cosmetically appealing for men and has similar demonstrated efficacy and safety profiles.34 Female-Pattern Androgenetic Alopecia. The 2% topical minoxidil formulation is indicated for female-pattern androgenetic alopecia of the frontoparietal areas with diffuse thinning. Interestingly, Lucky and colleagues35 evaluated minoxidil in a doubleblind, randomized, placebo-controlled study that demonstrated the superiority of the 5% formulation over the 2% formulation and placebo. Many clinicians will use the 5% formulation ‘offlabel’ in women. Another trial in Japanese women demonstrated efficacy of the lower-strength 1% solution available for use there.36 Off-Label Dermatologic Uses. A variety of dermatologic conditions involving hair loss have been treated with topical minoxidil, with varying success. Q57.5 These conditions include alopecia areata, congenital hypotrichosis, and loose anagen syndrome.29 Alopecia Areata and Androgenetic Alopecia. According to one study, topical 5% minoxidil was more effective than 1% minoxidil; the higher-strength formulation is recommended.37 Additional studies, using 3% and 5% concentrations, with up to 3 years’ follow-up, found that a subset of patients with alopecia areata had a cosmetically acceptable regrowth of hair.38,39 Overall, topical minoxidil has a relatively limited role in the therapeutic armamentarium for patients with alopecia areata; topical minoxidil can be use ‘off-label’ with oral medications such as spironolactone for females with androgenetic alopecia. Chronic use is typically required to sustain the clinical for both types of hair loss. Before Hair Transplantation. A recommendation for prehair transplantation use of topical minoxidil 5% is from a round-table discussion at the Ninth Annual Meeting of the International Society of Hair Restoration Surgery.40 The group suggested that the use of topical minoxidil before hair transplantation may improve the function of suboptimal follicles and with subsequent use may optimize survival of the transplanted follicles. Chemotherapy-Induced Alopecia. One small study of 22 women treated with minoxidil 2% solution while undergoing chemotherapy demonstrated statistically significant prolonged time until maximal hair loss, as well as faster recovery of hair regrowth after maximal loss. The agent was unable to truly change the course of the inevitable hair loss, however.41 Adverse Effects. Irritant dermatitis and allergic contact dermatitis each occur in less than 10% of cases treated with topical minoxidil. Hypertrichosis of skin other than the scalp can occur if there is inadvertent application to that site. Systemic absorption is minimal. An average of 1.4% of the applied dose is absorbed. For the standard 1-mL dose, this would result in 0.28 mg of systemic absorption. If minoxidil were to be applied to the entire scalp, a systemic dose in the range of 2.4 to 5.4 mg daily might be expected.31,42 Somewhat less inadvertent application (and

subsequent hypertrichosis) as well as systemic absorption may be expected from the foam vehicle versus the solution.34 Therapeutic Guidelines. All published studies for US Food and Drug Administration (FDA)-approved uses evaluated Rogaine 1 mL of solution, or half a capful of foam, applied to the scalp twice daily. Therapy needs to be continued indefinitely for maintenance purposes. The product is available OTC with various application options, including dropper, roll-on, and spray. Pregnancy Prescribing Status. Topical minoxidil is pregnancy prescribing class C. It is not recommended for pregnant or nursing women.

Bimatoprost Prostaglandin-mediated improvement in hair growth was discovered serendipitously when it was noted that patients treated with latanoprost (a topical synthetic prostaglandin analog) for glaucoma developed hypertrichosis of the eyelashes. Another similar topical ocular antihypertensive, bimatoprost, was also found to increase eyelash growth to a greater degree than latanoprost.43 Subsequently, a bimatoprost 0.03% formulation for dermal application at the base of the eyelashes has been FDA approved for the treatment of eyelid hypotrichosis. Treatment with bimatoprost 0.03% increases lash length, thickness, and pigmentation, with fewer AE than the eyedrop preparation.44 The primary mechanism of action is believed to be increasing the proportion of follicles in anagen phase at any given time. Stimulation of melanin production (without proliferation of melanocytes) is likely responsible for the increased pigmentation of the hairs.44 Likely via the same mechanism, darkening and pigmentation changes of the iris have been observed with intraocular use for glaucoma; this complication has not been commonly seen with dermatologic use.45,46 Another complication which has been described primarily in the setting of ophthalmic use for glaucoma is the ‘prostaglandin-associated periorbitopathy’, which is characterized by periorbital fat pad loss and deepening of the upper lid sulcus; this presentation may be more likely with bimatoprost than other prostaglandin analogs.47 Although the changes are rare, careful monitoring for this AE has been recommended, as it can be irreversible.48

Capsaicin Capsaicin is a compound derived from chili peppers that contributes their burning quality. The compound applied to the skin induces release of neuropeptides from the unmyelinated pain fibers. In particular, the stimulated release and subsequent (after 1 to 2 weeks of use) of substance P (one of the neuropeptides) from the nerve appears to be key to the efficacy of the agent. The primary use has been for management of post-herpetic neuralgia.

Anthralin Pharmacology

Drithocreme and Anthraderm are brands of anthralin available in a cream base with concentrations (between the two trade name products and generic formulations) of 0.1%, 0.25%, 0.5%, and 1%, in 50-g tubes. The base is composed mainly of petrolatum and water. Micanol (also available in 50-g tubes) is a form of anthralin formulated in a unique delivery system. The anthralin is encapsulated in a matrix of semicrystalline monoglycerides known as crystalip. The layers of the crystalline monoglycerides protect the anthralin from oxidation and promote its stability, providing also for fewer AE.49,50

CHAPTER 57

Mechanism of Action. Q57.6 Anthralin inhibits monocyte proinflammatory activity and induces extracellular generation of oxygen free radicals.51–53 The production of oxygen free radicals induces irritation, but after repeated applications tolerance to this irritation is developed. Anthralin also has anti-Langerhans cell effects.54 Clinical Use US Food and Drug Administration-Approved Indication Psoriasis—Chronic Plaque Type. Anthralin is approved for

the treatment of chronic plaque psoriasis. Anthralin was first synthesized in 1916. The natural product, chrysarobin, comes from the South American araroba tree. Anthralin has been most commonly used in the treatment of psoriasis, especially on relatively localized plaques resistant to other therapies. Anthralin has been combined with ultraviolet B (UVB) phototherapy with good results.55 Q57.7 Because of problems with staining and irritancy, anthralin has never been widely used in the United States. To overcome these AE, anthralin ‘short-contact therapy’ became a common way of dosing topical anthralin (see ‘Therapeutic Guidelines’ section). Off-Label Dermatologic Uses Alopecia Areata Q57.6. Anthralin has also been commonly

used for alopecia areata. The safety of anthralin makes it useful in children and in adults with extensive alopecia areata, including alopecia totalis. Growth of new hair may begin at 2 to 3 months, and approximately 25% of patients have cosmetically acceptable hair regrowth at 6 months.56 Q57.7 Short-contact anthralin therapy (sometimes referred to as ‘SCAT’) is recommended to avoid irritation, although some degree of irritation may be necessary for a therapeutic response in patients with alopecia areata.57 Adverse Effects. As previously mentioned, irritant contact dermatitis and staining of clothing, skin, hair, and nails are all commonly observed adverse reactions seen with anthralin therapy. Therapeutic Guidelines. Q57.7 The most common approach is to start with a lower concentration of anthralin, such as 0.1% or 0.25%. The anthralin is left on the treatment area for 10 to 20 minutes daily. The contact time is increased weekly until the total contact time before washing is 1 hour. This approach generally reduces cutaneous irritation. Nevertheless, staining continues to be a problem. A product that contains triethanolamine (CuraStain) is available to reduce the irritation and staining noted with anthralin. The product is sprayed on the skin before cleaning off the anthralin and applied again after the removal of the material.50,58 Over time, depending on the clinical response and the degree of irritation, the concentration can be increased to the 0.5% and 1.0% anthralin products. Pregnancy Prescribing Status. Anthralin is pregnancy prescribing category C. It is not recommended for pregnant or nursing mothers.

Aloe Vera Aloe vera has extensive popular support in the lay press for a wide variety of uses, but scientific evidence to support these uses is sparse. There have been anecdotal published reports suggesting aloe vera efficacy for acute frostbite,59,60 lichen planus,61–63 enhancement of postdermabrasion wound healing,64 psoriasis,65,66 and venous leg ulcers.67 Allergic contact dermatitis has been reported.

Miscellaneous Topical Agents

629

Brimonidine Pharmacology

Brimonidine 0.33% topical gel (Mirvaso) is supplied in a 30-g tube. A generic 0.15% and 0.2% solution is also available in 5-, 10-, and 15-mL bottles for ophthalmic use. Mechanism of Action. Brimonidine is a selective α2 adrenergic receptor agonist, which results in direct, potent vasoconstriction of small arterioles. This mediates its reduction in persistent facial erythema, as well as hemostatic properties. Clinical Use US Food and Drug Administration-Approved Indication Persistent Facial Erythema From Rosacea. In 2013, brimoni-

dine 0.33% gel was the first topical therapy to be FDA approved for the treatment of persistent facial erythema from rosacea. Randomized controlled trials demonstrated significant improvement in facial erythema by both patients and investigators.68,69 Sustained efficacy without significant tachyphylaxis through 12 months of daily use has been documented.70 Off-Label Dermatologic Uses Hemostasis During Surgical Procedures. Brimonidine has been

used in ophthalmic, sinus, and cutaneous surgery for intraoperative vasoconstriction and reduction of blood loss. One randomized controlled pilot study in Mohs patients taking anticoagulants demonstrated 68% less blood loss and a reduction in the need for electrocautery with preoperative application of brimonidine 0.33% gel to intact skin.71 Adverse Effects. Q57.8 The most common AE reported for brimonidine are rebound facial flushing (which can be worse than the patient’s baseline) and a burning sensation.69 Rebound erythema has been described with both short69,72 and longer-term use,73 and typically follows initial improvement in erythema after several hours. The symptoms are transient, lasting up to 12 hours, but may worsen with continued use of brimonidine, possibly caused by upregulation of α-receptors.74 These AE do generally resolve with discontinuation of the drug. True allergic contact dermatitis to brimonidine 0.33% gel has also been documented.75 Q57.9 When used in the perioperative setting for hemostasis, serious but reversible central nervous system (CNS) depression has been reported.76 In these two cases, application of larger amounts of brimonidine gel (10 g) under occlusion to open, oozing surgical wounds resulted in respiratory depression and somnolence requiring hospitalization. Both patients had improved back to their baseline status within 24 hours with supportive care. Similar CNS toxicity has been reported in the setting of combination brimonidine and timolol topical therapy for ulcerated hemangiomas in infants.77 Brimonidine’s propensity for CNS effects is likely related to its high lipophilicity, facilitating its crossing of the blood–brain barrier. Therapeutic Guidelines. Brimonidine 0.33% gel (Mirvaso) is applied daily to affected facial skin for management of persistent erythema. Pregnancy Prescribing Status. Brimonidine topical is pregnancy category B. Risk is not expected, especially given minimal systemic absorption.

Oxymetazoline Pharmacology

Oxymetazoline 1% cream (Rhofade) is available by prescription in a 30- or 60-g tube or pump. Oxymetazoline 0.05% solution is available over the counter in various nasal spray formulations.

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Mechanism of Action. Oxymetazoline is a selective α1 adrenergic receptor agonist, which mediates vascular smooth muscle contraction and subsequent vasoconstriction of small vessels in the skin. In addition to its vasoconstrictive effects, it has been demonstrated to have direct anti-inflammatory and antioxidant effects, in part by modulating metabolites of arachidonic acid.78 Clinical Use Dermatologic Uses US Food and Drug Administration-Approved Indication Persistent Facial Erythema From Rosacea. Q57.10 Oxymetazo-

line 1% cream was FDA approved for the treatment of persistent facial erythema from rosacea in 2017. Initial case reports topically using the OTC nasal spray formulation had suggested efficacy for facial erythema.79 Subsequent randomized controlled trials confirmed the superiority of daily application of the 1% cream over vehicle in producing a grade 2 or greater reduction in erythema from baseline using both the Clinician Erythema Assessment (CEA) and Subject Self-Assessment (SSA) for rosacea facial redness.80 Adverse Effects. The most commonly reported AE for topical oxymetazoline include application site dermatitis, pain, paresthesias, and pruritus. About 3% of patients experienced worsening of facial inflammatory lesions of rosacea, but rebound effect was noted in less than 1% of study participants.81 Therapeutic Guidelines. Oxymetazoline 1% cream is applied once daily to the affected areas for persistent facial erythema. Pregnancy Prescribing Status. Oxymetazoline 0.05% nasal spray is pregnancy prescribing category C; however, minimal risk of harm would be anticipated, given the very low level of systemic absorption.

Hydrogen Peroxide Hydrogen peroxide 40% solution (Eskata) has recently been FDA approved for topical treatment of seborrheic keratoses. Randomized controlled trials demonstrated clearance of 25% to 34% of treated lesions when compared with vehicle.82 The solution is supplied in a prefilled applicator and is applied to each lesion for a period of 20 seconds, which can be repeated for up to four cycles per lesion. Common AE include mild stinging and burning of the treatment site. Resultant hypo- or hyperpigmentation was relatively infrequent, occurring in 5% and 2% of treated patients, respectively.

Bibliography: Important Reviews and Chapters Topical Antioxidants Keller KL, Fenske NA. Uses of vitamins A, C, and E and related compounds in dermatology: a review. J Am Acad Dermatol. 1998;39(4Pt1):611–625.

Pinnell SR. Cutaneous photodamage, oxidative stress, and topical antioxidant protection. J Am Acad Dermatol. 2003;48(1):1–19. quiz 20–22. Topical Hemostatic Agents and Treatments for Hyperhidrosis Thomas I, Brown J, Vafaie J, Schwartz RA. Palmoplantar hyperhidrosis: a therapeutic challenge. Am Fam Physician. 2004;69(5):1117–1120. Other Topical Agents Derry S, Lloyd R, Moore RA, McQuay HJ. Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2009;4:CD007393. Kemény L, Ruzicka T, Braun-Falco O. Dithranol: a review of the mechanism of action in the treatment of psoriasis vulgaris. Skin Pharmacol. 1990;3(1):1–20. MacDonald Hull SP, Wood ML, Hutchinson PE, Sladden M, Messenger AG, British Association of Dermatologists. Guidelines for management of alopecia areata. Br J Dermatol. 2003;149(4):692–699. van Zuuren EJ, Fedorowicz Z. Interventions for rosacea: abridged updated Cochrane systematic review including GRADE assessments. Br J Dermatol. 2015;173(3):651–662.

References* 1. Lin JY, Selim MA, Shea CR, et  al. UV photoprotection by combination topical antioxidants vitamin C and vitamin E. J Am Acad Dermatol. 2003;48(6):866–874. 2. Murray JC, Burch JA, Streilein RD, Iannacchione MA, Hall RP, Pinnell SR. A topical antioxidant solution containing vitamins C and E stabilized by ferulic acid provides protection for human skin against damage caused by ultraviolet irradiation. J Am Acad Dermatol. 2008;59(3):418–425. 27. Shah NS, Lazarus MC, Bugdodel R, et al. The effects of topical vitamin K on bruising after laser treatment. J Am Acad Dermatol. 2002;47(2):241–244. 34. Olsen EA, Whiting D, Bergfeld W, et  al. A multicenter, randomized, placebo-controlled, double-blind clinical trial of a novel formulation of 5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2007;57(5):767–774. 44. Cohen JL. Enhancing the growth of natural eyelashes: the mechanism of bimatoprost-induced eyelash growth. Dermatol Surg. 2010;36(9):1361–1371. 51. Schmidt KN, Powda M, Packer L, Baeuerle PA. Anti-psoriatic drug anthralin activates transcription factor NF-kappa B in murine keratinocytes. J Immunol. 1996;156(11):4514–4519. 52. Mrowietz U, Falsafi M, Schröder JM, Christophers E. Inhibition of human monocyte functions by anthralin. Br J Dermatol. 1992;127(4):382–386. 68. Fowler J, Jarratt M, Moore A, et al. Once-daily topical brimonidine tartrate gel 0·5% is a novel treatment for moderate to severe facial erythema of rosacea: results of two multicentre, randomized and vehicle-controlled studies. Br J Dermatol. 2012;166(3):633–641. 81. Draelos ZD, Gold MH, Weiss RA, et al. Efficacy and safety of oxymetazoline cream 1.0% for treatment of persistent facial erythema associated with rosacea: Findings from the 52-week open label REVEAL trial. J Am Acad Dermatol. 2018;78(6):1156–1163. 82. Baumann LS, Blauvelt A, Draelos ZD, et  al. Safety and efficacy of hydrogen peroxide topical solution, 40% (w/w) in patients with seborrheic keratoses: results from two identical, randomized, double-blind, placebocontrolled, phase 3 studies (A-101-SEBK-301/302). J Am Acad Dermatol. 2018;79(5):869–877.

*Only a selection of references are printed here. All other references in the reference list are available online at www.expertconsult.com.

Web References Ascorbic Acid 1. Lin JY, Selim MA, Shea CR, et al. UV photoprotection by combination topical antioxidants vitamin C and vitamin E. J Am Acad Dermatol. 2003;48(6):866–874. 2. Murray JC, Burch JA, Streilein RD, Iannacchione MA, Hall RP, Pinnell SR. A topical antioxidant solution containing vitamins C and E stabilized by ferulic acid provides protection for human skin against damage caused by ultraviolet irradiation. J Am Acad Dermatol. 2008;59(3):418–425. 3. Traikovich SS. Use of topical ascorbic acid and its effects on photodamaged skin topography. Arch Otolaryngol Head Neck Surg. 1999;125(10):1091–1098. 4. Halperin EC, Gaspar L, George S, Darr D, Pinnell S. A doubleblind, randomized prospective trial to evaluate topical vitamin C solution for the prevention of radiation dermatitis. Int J Radiat Oncol Biol Phys. 1993;26(3):413–416. 5. Humbert PG, Haftek M, Creidi P, et  al. Topical ascorbic acid on photoaged skin. Clinical, topographical and ultrastructural evaluation: double-blind study vs. placebo. Exp Dermatol. 2003;12(3):237–244. 6. Fitzpatrick RE, Rostan EF. Double-blind, half-face study comparing topical vitamin c and vehicle for rejuvenation of photodamage. Dermatol Surg. 2002;28(3):231–236. 7. Sauermann K, Jaspers S, Koop U, Wenck H. Topically applied vitamin C increases the density of dermal papillae in aged human skin. BMC Dermatol. 2004;4(1):13. 8. Panich U, Tangsupa-a-nan V, Onkoksoong T, et al. Inhibition of UVA-mediated melanogenesis by ascorbic acid through modulation of antioxidant defense and nitric oxide system. Arch Pharm Res. 2011;34(5):811–820. 9. Ahmed NA, Mohammed SS, Fatani MI. Treatment of periorbital dark circles: comparative study of carboxy therapy vs chemical peeling vs mesotherapy. J Cosmet Dermatol. 2018. [Epub ahead of print]. 10. Dayal S, Sahu P, Jain VK, Khetri S. Clinical efficacy and safety of 20% glycolic peel, 15% lactic peel, and topical 20% vitamin C in constitutional type of periorbital melanosis: a comparative study. J Cosmet Dermatol. 2016;15(4):367–373. 11. Dayal S, Sahu P, Yadav M, Jain VK. Clinical efficacy and safety on combining 20% trichloroacetic acid peel with topical 5% ascorbic acid for melasma. J Clin Diagn Res. 2017;11(9):WC08–WC11. 12. Lin FH, Lin JY, Gupta RD, et al. Ferulic acid stabilizes a solution of vitamins C and E and doubles its photoprotection of skin. J Invest Dermatol. 2005;125(4):826–832. 13. Pinnell SR. Cutaneous photodamage, oxidative stress, and topical antioxidant protection. J Am Acad Dermatol. 2003;48(1):1–19. quiz 20–22. Vitamin E 14. Seyger MM, van de Kerkhof PC, van Vlijmen-Willems IM, de Bakker ES, Zwiers F, de Jong EM. The efficacy of a new topical treatment for psoriasis. Mirak. J Eur Acad Dermatol Venereol. 1998;11(1):13–18. Selenium

See reference 13. Zinc 15. Rostan EF, DeBuys HV, Madey DL, Pinnell SR. Evidence supporting zinc as an important antioxidant for skin. Int J Dermatol. 2002;41(9):606–611. 16. Morgan AJ, Lewis G, Van den Hoven WE, Akkerboom PJ. The effect of zinc in the form of erythromycin-zinc complex (Zineryt

lotion) and zinc acetate on metallothionein expression and distribution in hamster skin. Br J Dermatol. 1993;129(5):563–570. 17. Emonet-Piccardi N, Richard MJ, Ravanat JL, Signorini N, Cadet J, Béani JC. Protective effects of antioxidants against UVAinduced DNA damage in human skin fibroblasts in culture. Free Radic Res. 1998;29(4):307–313. 18. Sharquie KE, Al-Mashhadani SA, Salman HA. Topical 10% zinc sulfate solution for treatment of melasma. Dermatol Surg. 2008;34(10):1346–1349. Aluminum Chloride 19. Drysol for treatment of hyperhidrosis. Med Lett Drugs Ther. 1977;19(4):20. 20. Dworin A, Sober AJ. Unilateral segmental hyperhidrosis. Response to 20% aluminum chloride solution and plastic wrap. Arch Dermatol. 1978;114(5):770–771. 21. Boyvat A, Piskin G, Erdi H. Idiopathic unilateral localized hyperhidrosis. Acta Derm Venereol. 1999;79(5):404–405. 22. Reynolds K, Darrigrand A, Roberts D, et al. Effects of an antiperspirant with emollients on foot sweat accumulation and blister formation while walking in the heat. J Am Acad Dermatol. 1995;33(4):626–630. 23. Benohanian A, Dansereau A. Influence of an antiperspirant on foot blister incidence during cross-country hiking. J Am Acad Dermatol. 1999;41(4):655–656. Ferric Subsulfate (Monsel’s solution) 24. Wood C. Atypical reactions to Monsel’s solution. Am J Dermatopathol. 1981;3(1):97–99. 25. Scheman AJ, Severson DL. Medications Used in Dermatology. 8th ed. Philadelphia: Lippincott Williams and Wilkins; 2003:200– 201. Phytonadione (vitamin K1) 26. Elson ML. Topical phytonadione (vitamin K1) in the treatment of actinic and traumatic purpura. Cosmet Dermatol. 1995;8:25–26. 27. Shah NS, Lazarus MC, Bugdodel R, et al. The effects of topical vitamin K on bruising after laser treatment. J Am Acad Dermatol. 2002;47(2):241–244. 28. Cohen JL, Bhatia AC. The role of topical vitamin K oxide gel in the resolution of postprocedural purpura. J Drugs Dermatol. 2009;8(11):1020–1024. Minoxidil 29. Price VH. Treatment of hair loss. N Engl J Med. 1999;341(13):964– 973. 30. Li M, Marubayashi A, Nakaya Y, Fukui K, Arase S. Minoxidilinduced hair growth is mediated by adenosine in cultured dermal papilla cells: possible involvement of sulfonylurea receptor 2B as a target of minoxidil. J Invest Dermatol. 2001;117(6):1594–1600. 31. Katz HI, Hien NT, Prawer SE, Goldman SJ. Long-term efficacy of topical minoxidil in male pattern baldness. J Am Acad Dermatol. 1987;16(3Pt2):711–718. 32. De Villez RL. Androgenetic alopecia treated with topical minoxidil. J Am Acad Dermatol. 1987;16(3Pt2):669–672. 33. Roberts JL. Androgenetic alopecia: treatment results with topical minoxidil. J Am Acad Dermatol. 1987;16(3Pt2):705–710. 34. Olsen EA, Whiting D, Bergfeld W, et al. A multicenter, randomized, placebo-controlled, double-blind clinical trial of a novel formulation of 5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2007;57(5):767–774. 35. Lucky AW, Piacquadio DJ, Ditre CM, et al. A randomized, placebo-controlled trial of 5% and 2% topical minoxidil solutions in the treatment of female pattern hair loss. J Am Acad Dermatol. 2004;50(4):541–553. 36. Tsuboi R, Tanaka T, Nishikawa T, et al. A randomized, placebocontrolled trial of 1% topical minoxidil solution in the treatment 630.e1

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37. 38. 39. 40. 41. 42.

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of androgenetic alopecia in Japanese women. Eur J Dermatol. 2007;17(1):37–44. Fiedler-Weiss VC. Topical minoxidil solution (1% and 5%) in the treatment of alopecia areata. J Am Acad Dermatol. 1987;16(3Pt2):745–748. Price VH. Double-blind placebo-controlled evaluation of topical minoxidil in extensive alopecia areata. J Am Acad Dermatol. 1987;16(3Pt2):730–736. Price VH. Topical minoxidil in extensive alopecia areata, including 3-year follow-up. Dermatologica. 1987;175(suppl 2):36–41. Avram MR, Cole JP, Gandelman M, et  al. The potential role of minoxidil in the hair transplantation setting. Dermatol Surg. 2002;28(10):894–900. Duvic M, Lemak NA, Valero V, et al. A randomized trial of minoxidil in chemotherapy-induced alopecia. J Am Acad Dermatol. 1996;35(1):74–78. Franz TJ. Percutaneous absorption of minoxidil in man. Arch Dermatol. 1985;121(2):203–206.

Bimatoprost 43. Gandolfi S, Simmons ST, Sturm R, Chen K, VanDenburgh AM, Bimatoprost Study Group 3. Three-month comparison of bimatoprost and latanoprost in patients with glaucoma and ocular hypertension. Adv Ther. 2001;18(3):110–121. 44. Cohen JL. Enhancing the growth of natural eyelashes: the mechanism of bimatoprost-induced eyelash growth. Dermatol Surg. 2010;36(9):1361–1371. 45. Yoelin SG, Fagien S, Cox SE, et  al. A retrospective review and observational study of outcomes and safety of bimatoprost ophthalmic solution 0.03% for treating eyelash hypotrichosis. Dermatol Surg. 2014;40(10):1118–1124. 46. Zaleski-Larsen LA, Ruth NH, Fabi SG. Retrospective evaluation of topical bimatoprost and iris pigmentation change. Dermatol Surg. 2017;43(12):1431–1433. 47. Kucukevcilioglu M, Bayer A, Uysal Y, Altinsoy HI. Prostaglandin associated periorbitopathy in patients using bimatoprost, latanoprost and travoprost. Clin Exp Ophthalmol. 2014;42(2):126–131. 48. Sira M, Verity DH, Malhotra R. Topical bimatoprost 0.03% and iatrogenic eyelid and orbital lipodystrophy. Aesthet Surg J. 2012;32(7):822–824. Capsaicin

See Cochrane Database Systematic Review in Bibliography. Anthralin 49. Juhlin L. Nordic dithranol symposium – introduction. Acta Derm Venereol. 1992;192(suppl):5. 50. Harris DR. Old wine in new bottles: the revival of anthralin. Cutis. 1998;62(4):201–203. 51. Schmidt KN, Powda M, Packer L, Baeuerle PA. Anti-psoriatic drug anthralin activates transcription factor NF-kappa B in murine keratinocytes. J Immunol. 1996;156(11):4514–4519. 52. Mrowietz U, Falsafi M, Schröder JM, Christophers E. Inhibition of human monocyte functions by anthralin. Br J Dermatol. 1992;127(4):382–386. 53. Kemeny L, Ruzicka T, Braun-Falco O. Dithranol: a review of the mechanism of action in the treatment of psoriasis vulgaris. Skin Pharmacol. 1990;3(1):1–20. 54. Morhenn VB, Orenberg EK, Kaplan J, Pfendt E, Terrell C, Engleman EG. Inhibition of a Langerhans’ cell-mediated immune response by treatment modalities useful in psoriasis. J Invest Dermatol. 1983;81(1):23–27. 55. Carrozza P, Häusermann P, Nestle PO, Burg G, Böni R. Clinical efficacy of narrow-band UVB (311nm) combined with dithranol in psoriasis. An open pilot study. Dermatology. 2000;200(1):35– 39.

56. Fiedler-Weiss VC, Buys CM. Evaluation of anthralin in the treatment of alopecia areata. Arch Dermatol. 1987;123(11):1491– 1493. 57. Swanson NA, Mitchell AJ, Leahy MS, Headington JT, Diaz LA. Topical treatment of alopecia areata. Arch Dermatol. 1981;117(7):384–387. 58. Ramsay B, Lawrence CM, Shuster S, Bruce JM. Reduction of anthralin-induced inflammation by application of amines. J Am Acad Dermatol. 1990;22(5Pt1):765–772. Aloe Vera 59. McCauley RL, Heggers JP, Robson MC. Frostbite. Methods to minimize tissue loss. Postgrad Med. 1990;88(8):67–68. 73–77. 60. Heggers JP, Robson MC, Manavalen K, et  al. Experimental and clinical observations on frostbite. Ann Emerg Med. 1987;16(9):1056–1062. 61. Hayes SM. Lichen planus—report of successful treatment with aloe. Gen Dent. 1999;47(3):268–272. 62. Rajar UD, Majeed R, Parveen N, Sheikh I, Sushel C. Efficacy of aloe vera gel in the treatment of vulval lichen planus. J Coll Physicians Surg Pak. 2008;18(10):612–614. 63. Choonhakarn C, Busaracome P, Sripanidkulchai B, Sarakarn P. The efficacy of aloe vera gel in the treatment of oral lichen planus: a randomized controlled trial. Br J Dermatol. 2008;158(3):573–577. 64. Fulton Jr JE. The stimulation of post dermabrasion wound healing with stabilized aloe vera gel-polyethylene oxide dressing. J Dermatol Surg Oncol. 1990;16(5):460–467. 65. Syed TA, Ahmad SA, Holt AH, Ahmad SA, Ahmad SH, Afzal M. Management of psoriasis with aloe vera extract in a hydrophilic cream: a placebo-controlled, double blind study. Trop Med Int Health. 1996;1(4):505–509. 66. Choonhakarn C, Busaracome P, Sripanidkulchai B, Sarakarn P. A prospective, randomized clinical trial comparing topical aloe vera with 0.1% triamcinolone acetonide in mild to moderate plaque psoriasis. J Eur Acad Dermatol Venereol. 2010;24(2):168– 172. 67. Atherton P. Aloe vera: magic or medicine? Nurs Stand. 1998;12(41):49–52. 54. Brimonidine 68. Fowler J, Jarratt M, Moore A, et  al. Once-daily topical brimonidine tartrate gel 0·5% is a novel treatment for moderate to severe facial erythema of rosacea: results of two multicentre, randomized and vehicle-controlled studies. Br J Dermatol. 2012;166(3):633–641. 69. Fowler Jr J, Jackson M, Moore A, et  al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12(6):650–656. 70. Moore A, Kempers S, Murakawa G, et  al. Long-term safety and efficacy of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of a 1-year open-label study. J Drugs Dermatol. 2014;13(1):56–61. 71. Chen E, Patel RA, Kwak YJ, Huang CC. Randomized controlled pilot study of the preoperative use of brimonidine 0.33% topical gel for hemostasis in Mohs micrographic surgery. J Am Acad Dermatol. 2017;77(6):1114–1118. 72. Werner K, Kobayashi TT. Dermatitis medicamentosa: severe rebound erythema secondary to topical brimonidine in rosacea. Dermatol Online J. 2015;21(3). 73. Lowe E, Lim S. Paradoxical erythema reaction of long-term topical brimonidine gel for the treatment of facial erythema of rosacea. J Drugs Dermatol. 2016;15(6):763–765.

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74. Routt ET, Levitt JO. Rebound erythema and burning sensation from a new topical brimonidine tartrate gel 0.33%. J Am Acad Dermatol. 2014;70(2):e37–e38. 75. Bangsgaard N, Fischer LA, Zachariae C. Sensitization to and allergic contact dermatitis caused by Mirvaso (brimonidine tartrate) for treatment of rosacea – 2 cases. Contact Dermatitis. 2016;74(6):378–379. 76. Shagalov DR, Taylor D, Schleichert R, Weiss J, Weiss E. Association of central nervous system depression with topical brimonidine when used for hemostasis: a serious adverse event. JAMA Dermatol. 2017;153(6):575–577. 77. Gill K, Bayart C, Desai R, Golden A, Raimer P, Tamburro J. Brimonidine toxicity secondary to topical use for an ulcerated hemangioma. Pediatr Dermatol. 2016;33(4):e232–e234. Oxymetazoline 78. Beck-Speier I, Dayal N, Karg E, et  al. Oxymetazoline inhibits proinflammatory reactions: effect on arachidonic acid-derived metabolites. J Pharmacol Exp Ther. 2006;316(2):843–851. 79. Shanler SD, Ondo AL. Successful treatment of the erythema and flushing of rosacea using a topically applied selective

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alpha1-adrenergic receptor agonist, oxymetazoline. Arch Dermatol. 2007;143(11):1369–1371. 80. Baumann L, Goldberg DJ, Stein Gold L, et al. Pivotal trial of the efficacy and safety of oxymetazoline cream 1.0% for the treatment of persistent facial erythema associated with rosacea: findings from the second REVEAL trial. J Drugs Dermatol. 2018;17(3):290– 298. 81. Draelos ZD, Gold MH, Weiss RA, et  al. Efficacy and safety of oxymetazoline cream 1.0% for treatment of persistent facial erythema associated with rosacea: findings from the 52-week open label REVEAL trial. J Am Acad Dermatol. 2018;78(6):1156– 1163. Hydrogen Peroxide 82. Baumann LS, Blauvelt A, Draelos ZD, et al. Safety and efficacy of hydrogen peroxide topical solution, 40% (w/w) in patients with seborrheic keratoses: results from two identical, randomized, double-blind, placebo-controlled, phase 3 studies (A-101-SEBK-301/302). J Am Acad Dermatol. 2018;79(5):869–877.

PART XI

Injectable and Mucosal Routes of Drug Administration

58 Local Anesthetics GEOFFREY F.S. LIM, MICHAEL J. HUETHER AND DAVID G. BRODLAND

QUESTIONS Q58.1 What are some significant differences between commonly used injectable local anesthetics, including properties such as amide versus ester, lipophilicity, etc.? (Pg. 632)

Q58.12 What are the most common adverse effects caused by the procedure of injecting the anesthetic? (Pg. 639)

Q58.2 What are the advantages and limitations of liposomal bupivacaine? (Pg. 632)

Q58.13 Is lidocaine safe to use during pregnancy, and how does it compare for use in pregnancy with other injectable local anesthetics? (Pg. 641)

Q58.3 What is the mechanism of action for injectable and topical local anesthetics, including the effects on various sensory and motor nerves? (Pg. 634)

Q58.14 Concerning topical anesthetics for skin surfaces, (1) what is the most effective topical local anesthetic, and (2) how does the ‘eutectic’ concept ‘work’? (Pg. 641)

Q58.4 Which nerve fibers serve as nociceptors? (Pg. 634)

Q58.15 In what circumstances is there a risk of methemoglobinemia caused by the prilocaine component of eutectic lidocaine and prilocaine (EMLA)? (Pg. 642)

Q58.5 What techniques can be used to make injection of local anesthetic less painful? (Pg. 636) Q58.6 What is the gate control theory of pain, and how is it exploited in infiltrative anesthetic techniques? (Pg. 637) Q58.7 What are safe doses of lidocaine in tumescent anesthesia? (Pg. 637) Q58.8 What is the maximum dose of lidocaine in a single surgical setting to minimize the risk of systemic toxicity (both with and without epinephrine)? (Pg. 637)

Q58.16 What are the four potential benefits of having epinephrine present in injectable local anesthetics such as lidocaine? (Pg. 644) Q58.17 Is lidocaine with epinephrine safe to use on digits and other previously ‘prohibited’ sites such as nose, penis, and toes? (Pg. 646)

Q58.9 What is the treatment for lidocaine toxicity? (Pg. 638)

Q58.18 In what unique circumstances can patients experience unexpected and severe hypertension with local anesthesia injection? (Pg. 646)

Q58.10 How common is a true allergy to the anesthetic in local anesthetics (injectable and topical), and to which category of anesthetic are allergic reactions much more common? (Pg. 639)

Q58.19 What are the advantages and disadvantages for using diphenhydramine as an injectable local anesthetic, and how is the drug mixed in preparation for use as a local anesthetic? (Pg. 648)

Q58.11 What factors are commonly present with motor neuropraxia in facial nerve branches (i.e., temporal, marginal mandibular)? (Pg. 639)

A B B R E V I AT I O N S U S E D I N T H I S C H A P T E R CNS Central nervous system CYP Cytochrome P-450 EMLA Eutectic mixture of local anesthetic EMS Emergency medical system FDA Food and Drug Administration FTSG Full-thickness skin graft

IgE Immunoglobulin E PABA Para-aminobenzoic acid PUVA Psoralen plus ultraviolet A STSG Split-thickness skin graft TAC Tetracaine adrenaline (epinephrine) cocaine VMA Vanillylmandelic acid

631

632

PA RT XI

Injectable and Mucosal Routes of Drug Administration

Introduction Local anesthetics are used daily in almost every dermatologist’s practice. Whether applying a topical anesthetic before a cosmetic procedure or injecting the skin and subcutaneous tissues with a local anesthetic before excision of a skin cancer, dermatologists must be very familiar with the use of these agents. The pursuit of cost-effective care has been a major focus in recent years. Local anesthetics have been responsible for allowing many traditional hospital-based procedures to be performed in a less expensive outpatient setting. More importantly, this move away from general anesthesia has resulted in greater safety for patients.1 As dermatologists continue to expand the types of procedure performed in the office, mastering this important group of medications allows them to continue providing safe and effective local anesthesia (Table 58.1).

Injectable Local Anesthetics Lidocaine and Related Amide Anesthetics Local anesthetics were first used in medicine in the late nineteenth century. The first agent used, cocaine, was isolated in 1860 by Niemann.2 This drug was first used in clinical medicine in the field of ophthalmology by Koller in 1884, as a topical anesthetic.3 At the time, it was the only agent available and remained so until 1904, when procaine, a para-aminobenzoic acid (PABA) ester, was synthesized by Einhorn.4 It was not until 1948 that an amide local anesthetic, lidocaine, was synthesized.5 Lidocaine is now by far the most common local anesthetic in use today. Pharmacology Structure. Q58.1 Although many chemically diverse compounds have anesthetic properties, the local anesthetics used most commonly for infiltrative anesthesia are classically divided into two groups, esters (e.g., cocaine, procaine, tetracaine, benzocaine) and amides (e.g., lidocaine, mepivacaine, bupivacaine, etidocaine, prilocaine, ropivacaine). Members of both groups have an aromatic (lipophilic) portion, an intermediate chain (ester or amide), and an amine (hydrophilic) portion6 (Fig. 58.1). Structural variations in the aromatic and amine portions affect protein binding, potency, duration of action, and other aspects of clinical use. Specifically, lipophilicity appears to be correlated with the intrinsic potency of the anesthetic. For example, bupivacaine is highly lipophilic compared with lidocaine, and is also much more potent, with a longer duration of action.7 Chiral modifications of local anesthetics also carry their own pharmacodynamic, pharmacokinetic, and toxicity profiles. In general, the S-enantiomer is more potent and has a longer duration of action compared with the R-enantiomer or the racemic mixture of both forms.8 The S-form also tends to be less toxic. Ropivacaine and levobupivacaine are pure S-enantiomers that offer less neurotoxicity and cardiotoxicity, although their safety and efficacy have not been established in the pediatric population.9,10 Absorption. Absorption of lidocaine and all injectable local anesthetics into the blood is influenced by several factors: properties of the agent, presence of a vasoconstrictor in the injected solution, site of injection, quantity of drug injected, and technique of injection. Cocaine has relatively potent vasoconstrictive properties. All other local anesthetics have varying degrees of vasodilatory effects. Epinephrine is often added to local anesthetics for its

hemostatic effect. This vasoconstriction also delays absorption of these anesthetic agents, thereby prolonging the anesthetic effect (Table 58.2). Without epinephrine, the approximate duration of action of lidocaine is 30 to 60 minutes. With epinephrine, this duration can be extended to approximately 120 to 360 minutes.7 Bupivacaine, when combined with epinephrine, has a duration of action of up to 8 hours. Skin and subcutaneous tissues of the face and scalp exhibit higher significant absorption than the trunk or extremities owing to the increased relative density of blood vessels. Duration of anesthesia may be briefer in these highly vascularized areas. Also, if these anesthetic agents are injected too deeply into subcutaneous fat, they may give inadequate anesthesia, particularly on the scalp. The result is a requirement for larger volumes of local anesthetic injection, which in turn leads to increased systemic drug absorption. Incorrect infiltration technique may also lead to direct intravascular injection, risking systemic toxicity. Bioavailability. Protein binding is a property of local anesthetics that relates to the relative lipophilicity of the agent. Lidocaine is 60% to 80% protein bound and has an elimination half-life of 1.5 to 2.0 hours. Bupivacaine is 82% to 96% protein bound, with an elimination half-life of up to 5.0 hours.11 Animal studies suggest that lidocaine is widely distributed in all body tissues;12 however, each local anesthetic varies in rate and degree of penetration in various tissues and organs. Q58.2 The development of lipid nanoparticles used as delivery systems of both infiltrative and topical local anesthetics has enabled prolonged duration of action through modified rates of drug release and increased bioavailability, consequently reducing toxicity and improving therapeutic potency.13,14 Depending on the specific formulation, there may be a 2- to 400-fold increase in elimination half-life.15 Liposomal bupivacaine, in contrast with the more commonly used bupivacaine hydrochloride, may last up to 72 hours (see Table 58.2) and has been shown to be advantageous in prolonging postsurgical analgesia, reducing the need for opioids, minimizing hospitalization costs, and having an overall higher patient satisfaction compared with plain bupivacaine.14,16 However, liposomal bupivacaine is at least 10 times more expensive compared with bupivacaine hydrochloride, limiting its cost effectiveness and use in the outpatient dermatology setting.17,18 Metabolism. Amide and ester local anesthetics are metabolized differently. The amide class of local anesthetics, of which lidocaine is the prototype, is hydrolyzed by hepatic microsomal enzymes located in the endoplasmic reticulum of hepatocytes.19 Among the amides, there is variation in rate of metabolism in the following approximate order (listed from fastest to slowest):12 prilocaine, etidocaine, lidocaine, mepivacaine, bupivacaine. In patients with significant liver dysfunction, metabolism can be dramatically impaired, putting the patient at risk for systemic toxicity when relatively high volumes of an amide local anesthetic are used. Lidocaine is specifically metabolized by hepatic microsomal enzymes of the cytochrome P-450 (CYP) 3A4 system,19 which has significant implications regarding drug interactions and is discussed later in the Drug Interactions section. Ester local anesthetics are hydrolyzed very rapidly in the blood by pseudocholinesterase to form aromatic acids and amino alcohols. In fact, procaine has a plasma half-life of less than 1 minute.20 Its primary metabolite is PABA, a portion of which undergoes further metabolism in the liver. Patients with pseudocholinesterase deficiency have impaired metabolism of ester anesthetics.21 Approximately 4% of the population is partially deficient in this enzyme, potentially resulting in somewhat slow metabolism of these anesthetics. Approximately 0.1% of the population may

TABLE Drugs Discussed in This Chapter—Local Anesthetics 58.1

Drug

Common Trade Names

Drug Formulations

Articaine

Septocaine, Zorcaine, Orabloc

4% solution (with 1:100,000 epinephrine) 4% solution (with 1:200,000 epinephrine)

Bupivacaine

Marcaine, Sensoricaine

0.25% solution 0.25% solution (with 1:200,000 epinephrine)

Etidocaine

Duranest

1% solution 1%, 1.5% solution (with 1:200,000 epinephrine)

Lidocaine

Xylocaine

0.5%, 1%, 2% solution 0.5%, 1%, 2% solution (with 1:100,000 epinephrine) 0.5%, 1%, 2% solution (with 1:200,000 epinephrine)

Mepivacaine

Carbocaine, Polocaine

1%, 1.5%, 2%, 3% solution 3% solution (with 1:20,000 levonordefrin)

Prilocaine

Citanest

4% solution 4% solution (with 1:200,000 epinephrine)

Chloroprocaine

Nesacaine

1%, 2% solution

Procaine

Novocain

1% solution

Benadryl Injection

10 mg/mL (see text regarding dilution instructions)

Dibucaine

Nupercainal

1% ointment 0.5% cream

Lidocaine

Xylocaine, LMX 4, ELA-Max, Lidoderm

4% cream, solution, liposomes 2% viscous solution, jelly 2.5%, 5% ointment 10% oral spray 5% patch

Mixture of lidocaine and prilocaine

EMLA, Oraqix

2.5% lidocaine, 2.5% prilocaine cream, transdermal patch 2.5% lidocaine, 2.5% prilocaine gel

Benzocaine

Solarcaine, Lanacane, Americaine, Dermoplast

20% gel, solution, aerosol 1%–20% ointment, cream, paste 0.5%–8% lotion

Cocaine

(None)

4%, 10% solution

Pramoxine

Prax, Pramagel, Caladryl

1% cream, lotion, ointment, gel

Dyclone, Cepacol, Sucrets

0.5%, 1.0% solution, aerosol, lozenge

Diphenhydramine

Benadryl Itch Relief

1%, 2% cream 2% gel, spray, stick

Doxepin

Zonalon, Prudoxin, Xepin

5% cream

Zostrix, Capsin, Capzasin P, Zostrix HP, Capzasin HP,

0.025% cream, gel, liquid 0.035%, 0.075%, 0.1% cream

Many

1:100,000 or 1:200,000 dilution

Injectable Anesthetics Amide Local Anesthetics

Ester Local Anesthetics

Antihistamines Diphenhydramine

Topical Anesthetics Amide Local Anesthetics

Ester Local Anesthetics

Ketone Local Anesthetics Dyclonine

Antihistamines

Substance P Depletors Capsaicin

Vasoconstrictors Epinephrine

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CH3

H N CH3

N O CH3

CH3

Lidocaine O

O

CH3

H2N Benzocaine CH3

CH3 O N

N CH3

H Mepivacaine

• Fig. 58.1

Chemical structure of several local anesthetics.

have near complete deficiency of pseudocholinesterase, resulting in clinically significant difficulty clearing these anesthetic agents. However, the greatest clinical impact of pseudocholinesterase deficiency is prolonged effect of the neuromuscular blocking agent succinylcholine. Excretion. Renal excretion is the major route of elimination of local anesthetics from both classes. Lidocaine’s excretion is complex. The majority of the drug passes through the liver, where it is metabolized, and then is excreted into bile. Because very few metabolites are found in feces, it is believed that the lidocaine metabolites are then reabsorbed from the gastrointestinal tract and excreted in the urine.22 Lidocaine metabolites represent the majority of excreted drug, with less than 10% of the injected lidocaine being excreted unchanged by the kidney.23 Only 2% of procaine is excreted unchanged in the urine. The majority of the drug is excreted as its primary metabolite, PABA. Mechanism of Action Normal Physiology of Nerve Conduction. Q58.3 To understand

the mechanism of action of local anesthetics, one must understand the normal physiology of nerve conduction. At rest, nerve axonal membranes have a transmembrane electric potential (290–260 mV). This potential is maintained by an active transport sodium– potassium pump that continually pumps sodium ions into the extracellular space. Distinct sodium ion channels remain closed in this resting state, resulting in a negatively charged intracellular space (axonal cytoplasm). When a nerve is stimulated, sodium channels open, allowing the massive influx of sodium ions. This sodium influx depolarizes the membrane toward the sodium equilibrium potential (140 mV), reversing the internal negative charge

to a positive charge. Subsequently, sodium channels inactivate and potassium channels open, allowing the egress of potassium ions. The active transport sodium–potassium pump again restores the baseline transmembrane potential (290–260 mV). It is through this process that nerve impulses are transmitted down axons and between cells. Preventing Nerve Depolarization. Local anesthetics block conduction in nerves by minimizing or preventing the influx of sodium ions, thereby preventing depolarization (Table 58.3).24–26 This effect is thought to be mediated by the induction of a conformational change in voltage-sensitive sodium channels after binding. The lipophilic portion of the drug allows penetration of the cell membrane, whereas the hydrophilic portion is thought to interact with the sodium channels on the inner surface of the cell membrane.27 Subcategories of Nerve Fibers. Q58.4 Although local anesthetics work on all nerves, there are different propensities to block conduction, depending on nerve fiber characteristics. Among the myelinated nerves, smaller-diameter fibers are more sensitive to blockade by local anesthetics.28 Small fibers that are relevant to the dermatologist carry pain and temperature sensations (type A, δ fibers), whereas larger, and hence relatively more resistant, fibers carry touch and pressure sensation (type A, α fibers). Aδ and C fibers, the latter being small unmyelinated nerves, are both nociceptors with free nerve endings that respond to potentially injurious or noxious stimuli.29 Aδ fibers signal the initial, sharp, localized pain, whereas C fibers represent more diffuse, dull, aching pain.30 The largest and most resistant fibers control proprioception and motor function (type A, α fibers). Myelinated fibers are more resistant to anesthetics than unmyelinated fibers. For this reason, it is prudent to remind patients that after being anesthetized they may still feel pressure, but they should not feel pain. Remember that temporary motor paresis may occur either if high volumes of local anesthetic are used or if deep placement of the local anesthetic occurs in an area where deeper motor fibers are present under the more superficial sensory cutaneous nerves. This temporary motor paresis may be seen commonly when anesthetizing skin on the temple overlying the temporal branch of the facial nerve. Clinical Use US Food and Drug Administration-Approved Indications. Food and Drug Administration (FDA)-approved dermatologic indications for use of injectable local anesthetics include infiltrative anesthesia and regional nerve blocks (Box 58.1).31–72 Examples of office-based cutaneous procedures include, but are not limited to, biopsies, excisions, wound closures, tissue rearrangement, skin grafting, cauterization, nonablative laser, and ablative skin resurfacing. For more complex procedures, such as full-face ablative laser resurfacing or follicular unit hair transplantation, local anesthesia may be combined with topical and nerve block anesthesia or tumescent local anesthesia, respectively.68 Among the different indications for injectable anesthetics, the method of anesthesia (i.e., local infiltration, regional nerve block, or tumescent anesthesia) is often dictated by the nature of the procedure. For instance, for highly vascularized areas of the face or scalp, local infiltration of anesthetic combined with epinephrine is preferred to induce vasoconstriction and limit intraoperative hemorrhage. Regional blocks are ideal for larger operative fields and require fewer injections with less tissue distortion and taughtness.

TABLE Key Pharmacology Concepts—Commonly Used Injectable Local Anesthetics 58.2

Bupivacaine

Mepivacaine

Procaine

Diphenhydramine

Onset of action (minutes)

> clarithromycin

Strong CYP3A4 inhibitors which may ↑ lidocaine levels and potential toxicity

Imidazole, triazole antifungals

Ketoconazole >> itraconazole

same

Calcium channel blockers

Diltiazem, verapamil

same

HIV-1 protease inhibitors

Ritonavir, indinavir >> saquinavir, nelfinavir

same

Nutritional products

Grapefruit, grapefruit juice

same

Fluoroquinolones

Ciprofloxacin

Weak CYP3A4 inhibitors which may ↑ lidocaine levels and potential toxicity (to lesser extent)

Antidysrhythmics

Amiodarone

same

H2 antihistamines

Cimetidine

same

SSRI antidepressants

Fluoxetine, fluvoxamine

same

Anticonvulsants

Phenytoin, carbamazepine, phenobarbital

Strong CYP3A4 inducers—may ↓ lidocaine levels with potential loss of efficacy (Note- given delay in CYP inducer effect, relevant mainly to long-term use topical lidocaine products)

Rifamycin

Rifampin, rifabutin, rifapentine

Strong CYP3A4 inducer (rifampin), moderate (rifapentine), weak (rifabutin)

Lower-Risk Drug Interactions

The dramatic increase in number of drug interactions in medicine requires some degree of selectivity in these tables (common usage, relative risk, focus on outpatient treatment) aOverall highest-risk drug interactions indicated in bold italics. CYP, Cytochrome P-450; HIV-1, human immunodeficiency virus type 1; SSRI, selective serotonin reuptake inhibitor. Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. (https://www.wolterskluwercdi.com/facts-comparisons-online/); Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications; 2019. (http://www.hanstenandhorn.com/).

topical application of lidocaine to mucosal surfaces, widespread dermatoses, or injured skin.75–77 Blood levels of lidocaine correlate with distinct clinical signs and symptoms (Table 58.5)78 relating to toxicity primarily involving the central nervous system (CNS) and cardiovascular system. CNS toxicity can involve any of the following: drowsiness, circumoral paresthesia, lingual paresthesia, tinnitus, nystagmus, ataxia, hallucinations, twitching, restlessness, seizures, coma, or apnea.79 Note that the clinical signs do not necessarily progress in this sequence. For example, if a large volume of lidocaine is delivered intravascularly, seizures may be the first sign of toxicity noted.79 Complicating matters is the overlap between the signs and symptoms of lidocaine toxicity and the systemic effects of epinephrine. Anxiety, restlessness, and tremor may be caused by significant systemic levels of either drug. Given that the lidocaine dose limit has not been exceeded, these signs and symptoms can be safely assumed to be from the epinephrine. The absence of tinnitus and circumoral paresthesias also supports the diagnosis that the discusssed effects are indeed caused by epinephrine. Q58.9 Treatment starts with recognition of the anesthetic toxicity, discontinuing further use of local anesthetics, and observing for progressive symptoms of lidocaine toxicity. If clinical signs and symptoms of toxicity suggest midrange toxic blood levels (5–8 µg/ mL), treatment may be best accomplished by admission to hospital for observation. Seizures are treated by the following steps: establishing an airway, delivering oxygen, administering lorazepam or diazepam, and simultaneously activating the emergency medical

TABLE Lidocaine Blood Levels and Corresponding 58.5 Signs and Symptoms of Toxicity136

Blood Levels

Signs and Symptoms of Toxicity

1–5 µg/mL

Increased anxiety Talkativeness Tinnitus Circumoral numbness Lightheadedness Nausea and vomiting Metallic taste Diplopia

5–8 µg/mL

Nystagmus Slurred speech Localized muscle twitching Fine tremors

8–12 µg/mL

Focal seizure activity, with potential progression to tonic-clonic seizures Cardiopulmonary depression

20–25 µg/mL

Cardiopulmonary arrest Coma

service (EMS). Intravenous lipid emulsion (20%) infusion has been used safely and effectively to improve survival and reverse the cardiovascular and neurologic symptoms of local anesthetic tocixicity.80 This agent is typically administered in the emergency room or hospital setting.

CHAPTER 58

• BOX 58.2

A Simple Formula To Calculate Maximum Allowable Volume of Local Anesthetics

Maximum allowable dose (mg/kg) × weight (kg)/10 × 1/concentration of local anesthetic (%) = volume of anesthetic (mL) Maximum allowable doses: Lidocaine without epinephrine = 3 mg/kg Lidocaine with epinephrine = 7 mg/kg Bupivacaine with or without epinephrine = 2 mg/kg From Walsh K, Arya R. A simple formula for quick and accurate calculation of maximum allowable volume of local anaesthetic agents. Br J Dermatol. 2015;172(3):825–826.

The effects of lidocaine on the cardiovascular system are attributed to blocking sodium channels, which leads to decreased cardiac contractility in a ratio proportional to their potency, bupivacaine being roughly four times more potent than lidocaine.81 With lidocaine there is a progressive deterioration, with increasing blood levels going from hypotension (because of sympathetic blockade), to bradycardia, and finally respiratory depression.82 Bupivacaine toxicity may be different, with potentially fatal dysrhythmias (ventricular fibrillation) appearing as the first sign of cardiac toxicity. This may be attributed to the fact that bupivacaine dissociates more slowly or incompletely from the sodium channels once in the resting state.83 Unfortunately, even although the potency of bupivacaine is more than four times greater than that of lidocaine, its potential for cardiac toxicity is proportionately that much higher.81,84 As a rule, rare instances of cardiac toxicity require hospitalization for circulatory support. To minimize the risk of local anesthetic systemic toxicity, the following recommendations have been proposed:70 1. The use of the lowest effective dose of local anesthetic. 2. Before injection, the needle or catheter should be aspirated to avoid injection of the drug directly into a vessel. 3. The use of incremental injections of anesthetic. 4. Monitoring for signs of early toxicity by continually assessing and communicating with the patient. 5. Using a newly established simple formula to calculate the maximum allowable volume of two of the most common local anesthetic agents used in dermatologic procedures (Box 58.2).85 For instance, if the maximal dose for lidocaine with epinephrine is 7 mg/kg and the concentration of lidocaine is 1%, then the maximal volume of lidocaine that may be safely injected into a 70 kg patient is 49 mL. Allergic Reactions. Q58.10 Allergic reactions have been estimated to make up less than 1% of all adverse reactions to local anesthetics.86–88 They may be attributed to the anesthetic itself (true anesthetic allergy) or to preservatives such as parabens and sulfites.89 Esters have been much more commonly shown to cause allergic reactions; this is one of the primary factors that led to a major decline in the use of ester anesthetics. Allergic reactions to amides are much rarer.90 The two types of allergic reaction to local anesthetics are anaphylactic reactions (type I) and delayedtype hypersensitivity reactions (type IV). The most serious are anaphylactic reactions, which may be life threatening. These reactions are mediated by immunoglobulin E (IgE) and are often heralded by urticaria, angioedema, and bronchospasm (wheezing). If these signs occur within 1 to 2 hours of anesthetic injection, they support the diagnosis of anaphylaxis.90 A practical clue for assistance in rapidly distinguishing anaphylactic hypotension (in the absence of skin findings) from vasovagal reactions or dysrhythmias

Local Anesthetics

639

is the pulse. In anaphylaxis the patient is tachycardic, whereas in vasovagal reactions the patient is bradycardic, and, finally, in dysrhythmias the pulse is irregular.91 If the patient develops signs of respiratory or hemodynamic compromise, the EMS should be activated as supportive measures are instituted. In patients who present to the office with a history of ‘caine’ allergy, a detailed history of the previous reaction is necessary. Important information used to determine the nature of the reaction includes agents used, quantity administered, route given, presence of vasoconstrictors or preservatives, type of symptoms and signs experienced, time course, concomitant medications, past medical history, and preceding episodes.91 This information may be more reliably obtained from the healthcare provider who witnessed the reaction. This physician or dentist may be able to offer alternative anesthetics that have been used safely for that particular patient in the past. If unable to establish that the reaction was not allergic in nature, the patient should be referred for skin testing and incremental challenge. It has been suggested from limited patch-testing data that there is no cross-reaction between amides and esters.92 The practice of simply switching classes in patients with anaphylactic reactions has been recommended by some to avoid future hypersensitivity reactions. Unfortunately, this class switching has never been proved to be completely safe with regard to anaphylactic reactions. Thus, thorough evaluation by an allergist is recommended if the patient had a prior anaphylactic reaction.91 If no safe local anesthetic can be determined, infiltration of injectable 1% diphenhydramine93–95 or bacteriostatic normal saline96,36 can provide reasonable local anesthesia in selected instances. Motor Nerve Paresis and Neuropraxia. Q58.11 Motor nerve paresis and neuropraxia are consequences of surgical intervention and most often occur in ‘danger zones,’ such as those containing the temporal and marginal mandibular branches of the facial nerve. Transient motor nerve paresis can be seen with infiltration of local anesthetic in these regions and should resolve within 24 hours.97 Neuropraxia is also a temporary conduction deficit of motor nerves, although it may last up to 6 months and is largely caused by stretching or trauma of the nerve.98 The temporal nerve is most susceptible to conduction deficits by infiltration of local anesthesia as it crosses over the zygomatic arch, lying superficial to the deep temporalis fascia.99 This deficit manifests as unilateral frontalis paralysis and contributes to eyebrow ptosis. The marginal mandibular nerve is most susceptible 2 to 3 cm inferolateral to the oral commissure as it crosses the mandible, and paresis or injury results in facial asymmetry upon smiling (lip depressors, risorius, and platysma muscles), inability to protrude the lower lip (mentalis muscle), and drooling.100 Epinephrine Effects. Although epinephrine is not a local anesthetic, its effects are often included in a discussion of local anesthetic AE because they can be difficult to distinguish from one another. Transient or minor reactions frequently attributable to epinephrine include anxiety, headache, tremor, restlessness, and palpitations. Epinephrine is typically implicated as the cause of these symptoms when the total dose of anesthetic is well within the safe ranges listed in Table 58.2. These epinephrine effects may be mitigated by the use of low-dose sublingual diazepam, but generally improve or resolve spontaneously in a very short time. Epinephrine is discussed in detail later in this chapter. Reactions Related to Injection Procedure. Q58.12 Vasovagal reactions are not caused by an effect of the local anesthetic, but rather to unpleasant emotional or physical stimuli. These have a characteristic pattern that includes diaphoresis, lightheadedness,

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hypotension, and most importantly bradycardia. Immediate measures to treat such a reaction include supine positioning with leg elevation (Trendelenburg position), smelling salts, and a cool moist towel to the forehead. For vasovagal reactions not responding to these measures, atropine 0.4 mg delivered subcutaneously has been recommended.101 Local injection of nearly any substance can lead to hematoma, ecchymosis, nerve laceration, or infection, all of which may occur with the injection of local anesthetics. Drug Interactions. Lidocaine is metabolized by the hepatic microsomal enzymes of the cytochrome CYP3A4 system. Drugs that induce CYP3A4 may theoretically increase lidocaine clearance and reduce lidocaine blood levels.102 This would have no significant implications for dermatologic use because rapid clearance of systemically absorbed lidocaine would only enhance the safety profile of its use. However, CYP3A4 inhibitors may theoretically reduce lidocaine clearance and accordingly increase lidocaine blood levels21 (Table 58.4). A list of CYP3A4 inhibitors and inducers has been published.21 The authors recommend reducing doses of lidocaine for tumescent anesthesia (by 30%–40% in females and 10%–20% in males) when used in the presence of drugs that interfere with metabolism of lidocaine. With in-office excisional surgery or Mohs micrographic surgery, the volume of anesthetic used rarely approaches that capable of producing toxic blood levels. However, when administering large volumes of infiltrative anesthesia, it seems prudent to incorporate dosage reductions as previously suggested in patients who are on the various CYP3A4 inhibitors. Table 58.4 lists the most important drug interactions involving lidocaine. Some medications that have been reported to cause problems when given with lidocaine, either because of alterations in drug levels or by potentiating the tissue-specific effect of either agent, include102 digitalis, disopyramide, ephedrine, isosorbide dinitrate, mexiletine, pentobarbital, phenytoin, propafenone, and tocainide. In general, such case reports resulted from intravenous (IV) boluses of lidocaine, not after local infiltration. It should be remembered that improper injection technique can lead to inadvertent intravascular injection, effectively delivering an IV bolus of drug. Therapeutic Guidelines General Guidelines for Use. Although lidocaine is the most com-

mon local anesthetic in use today, other agents have valuable properties. Mepivacaine is very similar to lidocaine in onset and duration of anesthesia, but there is no dermatologic application for which the use of mepivacaine has clearly been shown to be advantageous. However, one study compared 0.9% saline, 1% prilocaine, 1% lidocaine, 1% mepavacaine, and 1% procaine for intradermal anesthesia and found that although all agents delivered a similar depth of anesthesia, mepivacaine was the least painful on injection.103 Although this finding was statistically significant, its clinical significance is uncertain. Technique of injection is far more important in the reduction in pain from local anesthetic injections than is the choice of local anesthetic. Bupivacaine offers prolonged duration of anesthesia, as much as four times the duration of plain lidocaine,104 although some feel its onset of action may be slower. This long duration of action is partially accounted for by the fact that the drug is very lipid soluble. In general, more lipid-soluble agents

are more potent, and this increased potency correlates with increased potential for both CNS toxicity and cardiovascular toxicity.9 Although this greater potency and prolonged duration of action have obvious advantages, the significantly increased pain associated with injecting this agent undermines these potential advantages. Mixing a rapid-onset/short-duration local anesthetic with a delayed-onset/long-duration anesthetic is now a common practice. Although it was previously shown that combining commercial preparations leads to unpredictable effectiveness,105 several randomized controlled trials comparing mixtures of local anesthetics have more recently proven to have acceptable safety profiles and effectiveness in both local infiltration and nerve block anesthesia.106–111 A significant trade-off of mixing two anesthetics is the inevitable dilution of the concentration of each agent being mixed, thereby reducing the anesthetic potency. Logically, if such a mixture is deemed appropriate in a given patient, the clinician can use the higher concentration of each anesthetic (e.g., 1:1 mixture using 2% lidocaine results in 1% final concentration). Utilization of mixtures and method of mixing vary in clinical practice, and current data remains insufficient when comparing use of anesthetic mixtures to that of single agents. Addressing the Lidocaine Shortage. In 2017, the United States began to experience a nationwide shortage of lidocaine with epinephrine.112 This is a function of many companies discontinuing their manufacturing of lidocaine with epinephrine (leaving only two pharmaceutical companies responsible for production) and an epinephrine shortage that resulting in a manufacturing bottleneck.112 In addition to the limited supply, the shortage is exacerbated by current practices that inflate the demand for the anesthetic. For instance, 20-mL multidose vials (MDV) of lidocaine with epinephrine have been reported as being discarded after using 2 to 5 mL for a small dermatologic procedure on a single patient.112 Although such policies are aimed at optimizing patient safety, the use of MDV in clinical practice has proven safe, without any evidence of bacterial or fungal contamination with the last dose of a MDV.113 To address this shortage and use the supply of lidocaine with epinephrine without compromising patient care, the following are recommended:112 1. That 1.5 mL is drawn up instead of 3 mL of lidocaine with epinephrine for biopsies. This decreases usage by 50%. 2. To mix 1% lidocaine 1:100,000 epinephrine with normal saline in a 1:1 mixture, producing a 0.5% 1:200,000 mixture. This also decreases usage by 50% and is consistent with the concentration that is available commercially, maintaining good vasoconstriction in both magnitude and duration of hemostasis.114 3. To refrain from wasteful practices, which include discarding unused prefilled syringes of lidocaine with epinephrine at the end of the day as well as discarding MDV. Although it has been argued that prefilled lidocaine syringes remain safe to use for up to 4 weeks after preparation, the instability of epinephrine after mixture with lidocaine limits their use to within 1 to 2 weeks.115,116 4. The use of lidocaine without epinephrine when possible. However, as discussed, plain lidocaine causes vasodilation, which increases cutaneous blood flow and blood loss at the site of injection, shortens the duration of anesthesia, complicates visualization of the operative field, and increases the risk for hematomas and infection.

CHAPTER 58

Use of Local Anesthetics During Pregnancy. Q58.13 (See Chapter 65 for additional information.) The use of local anesthetics during pregnancy should be considered cautiously, but is generally acceptable only in amounts necessary to provide adequate anesthesia.117,118 Lidocaine is classified as FDA pregnancy risk category B, indicating no risk to the human fetus, despite possible animal risk; or no risk in animal studies, whereas human studies have not been performed.119 Although lidocaine is generally thought to be safe in pregnancy, bupivacaine and mepivacaine are relatively contraindicated owing to the risk of fetal bradycardia.120 Ideally, infiltrative lidocaine should be reserved for urgent medical procedures, and those that are not urgent are recommended to be postponed until after delivery or at least after the second trimester.70 Recommendations for use of local anesthetics in pregnancy include the following:119 1. Avoiding use during organogenesis (15–56 days of gestation) when possible; 2. Minimizing doses of drug delivered; 3. Remaining alert for vasovagal reactions, which may occur at a higher rate during pregnancy; 4. Positioning the patient on her left side to avoid vena caval and aortic compression; 5. Using lidocaine and avoid mepivacaine and bupivacaine. Epinephrine is classified as FDA pregnancy risk category C, indicating that risk cannot be ruled out, human studies are lacking, and animal studies may or may not show risk, but benefits may justify potential risk.119 Although largely theoretical, caution should be exercised in the first trimester of pregnancy because placental blood vessels may be susceptible to the α-adrenergic properties of epinephrine and potentially result in an increase in fetal malformation.117 Despite this, it is believed to be unlikely that doses used in dermatologic surgery would have a significant effect over the endogenously produced epinephrine resulting from anxiety.121 In addition, if epinephrine allows a procedure to be performed more quickly and with the use of less anesthetic, its use may be justified.121 Although a set of general guidelines is represented, it is generally prudent to discuss the use of any medications in pregnancy with the patient’s obtetrician/delivering physician whenever a question arises.

Topical Anesthetics The greatest change in the area of local anesthesia has been the evolution of topical anesthetics. In the past 3 decades, there have been a number of new formulations of topical lidocaine, several of which are now available without a prescription. However, these new formulations which will be discussed have similar profiles, attributes, and risks of use to the prototype topical anesthetic, eutectic lidocaine and prilocaine (EMLA).

Eutectic Lidocaine and Prilocaine Topical anesthesia has been used for many years on mucosal surfaces because of the relative ease of penetration of topical agents on mucosa. However, the keratinized stratum corneum has been a major barrier to using topical anesthetics on normal skin. The use of previous formulations resulted in significant dermatitis, systemic toxicity, or inadequate local analgesia.122 EMLA is a cream formulation of lidocaine and prilocaine that can deliver adequate skin analgesia. The net result is either reduction of pain

Local Anesthetics

641

from subsequent needle puncture or even removal of the need for injectable anesthesia altogether. Pharmacology Absorption. Q58.14 The feature that makes EMLA unique is

the eutectic mixture of its components, lidocaine 2.5% and prilocaine 2.5%. Mixing the crystalline forms of each in a 1:1 ratio gives this combination a lower melting point than either agent alone; this is known as a ‘eutectic’ mixture.123,124 Thus, the combination is a liquid at room temperature and is subsequently able to be suspended in an oil-in-water emulsion.125 It is this highly concentrated liquid combination that promotes enhanced penetration over the crystalline form of either drug individually in a cream base.125 The polyoxyethylene fatty acid emulsifiers present within EMLA also allow for enhanced absorption.126 The amount of EMLA systemically absorbed is directly related to the duration and surface area of application.125 Skin blood flow, skin thickness (especially the stratum corneum), and the presence of skin pathology lead to altered absorption, in addition to affecting the onset of action, efficacy, and duration of action of EMLA.127 Regional variation in absorption has also been noted, with faster absorption occurring on the face. Techniques such as tape stripping, degreasing with acetone, laser ablation, occlusion, heat, and iontophoresis enhance anesthetic absorption.128–131 Specifically, occlusion and longer duration of application increase EMLA’s penetration and efficacy.132-134 Metabolism and Excretion. Prilocaine is metabolized by hepatic microsomal CYP enzymes in a fashion similar to lidocaine, but at a faster rate.135 Extrahepatic metabolism has been suggested by animal experiments.136 Prilocaine is excreted as metabolites via the kidney, with less than 1% of the drug renally excreted unchanged.13 Clinical Use US Food and Drug Administration-Approved Indications. The

FDA-approved dermatologic indication for EMLA is for topical analgesia of normal intact skin (Box 58.3).125,137–156 Skin Surgery. If applied as directed under an occlusive dressing, such as Tegaderm or cellophane, in a quantity of 1 to 2 g/10 cm2, the onset of significant analgesia occurs by approximately 60 minutes. Dermal analgesia increases for up to 3 hours if the EMLA is continuously occluded, and should persist for up to 1 to 2 hours after removal of the cream.125 Inadequate application or occlusion can contribute to inadequate analgesia. For this reason, a single-unit-dose package (EMLA patch) has been developed to simplify application. Patient instruction regarding proper use of EMLA is paramount for obtaining maximal analgesia with this product, particularly when the cream formulation is used. Depth of analgesia obtained with EMLA is important to address with regard to skin surgery. It has been shown that the depth of analgesia increases with increasing duration of application, up to a maximum of 5 mm. After a 90-minute application, this analgesia lasts for 30 minutes. After a 120-minute application, a 5-mm depth of analgesia lasts for 60 minutes.139 Even after removal of topical anesthesia, dermal analgesia continues secondary to accumulation of drug in the stratum corneum.140,141

642

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Injectable and Mucosal Routes of Drug Administration

EMLA has been successfully used to eliminate pain in 61% of children when applied for 1 hour before scalpel removal of molluscum, even in the setting of atopic dermatitis.143,144 However, in children it has not been shown to reduce the pain of routine vaccinations.145 Superficial shave excisions and punch biopsies may be possible in some patients with adequate preoperative application of EMLA. In one report evaluating excisional biopsies, curettage, and electrosurgery, EMLA was found to provide effective anesthesia in 87% of patients146 if applied 110 minutes before surgery, using either the cream or the patch formulation. Although reports such as these are encouraging, practical experience suggests that it is common for patients to require supplemental infiltrative anesthesia to ensure that these procedures are totally pain free. When such supplemental injections are required, they are much better tolerated owing to the degree of analgesia already achieved by the use of EMLA. Laser Surgery. EMLA has been widely used as preoperative analgesia before treating port wine stains.147,148 It is now being used for anesthesia before laser-assisted hair removal.149 Debridement of Leg Ulcers. EMLA has also been used to achieve analgesia during leg ulcer debridement and has been shown to reduce the number of debridement sessions required to clean ulcers.150,151 As with application to any open skin (which is not FDA approved), the clinician should consider the possibility of increased systemic absorption of both anesthetic components of the EMLA formulation.152 Off-label Dermatologic Uses Postherpetic Neuralgia. Postherpetic neuralgia has been treated

with EMLA cream with temporary improvement of variable duration.92–95 Although effective at once-daily application, the typical large size of the area to be treated and the need for occlusion limit the routine use of EMLA in this situation. Adverse Effects. AE caused by EMLA cream can be divided into systemic effects and local effects. Systemic Effects—Methemoglobinemia. Q58.15 The most serious AE of EMLA is methemoglobinemia. This is a unique AE of prilocaine. In this condition a metabolite of prilocaine, O-toluidine, is thought to cause oxidation of hemoglobin to methemoglobin.157 This oxidized (ferric) form of hemoglobin cannot carry oxygen and makes the release of oxygen from normal ferrous hemoglobin less efficient. The final result is tissue hypoxia. The normal methemoglobin concentration is 1% of total hemoglobin. Methemoglobin levels between 15% and 30% result in signs of cyanosis.158 Dyspnea, tachycardia, and headache are observed at levels of 30% to 50%, whereas lethargy and coma result from levels greater than 50%.159 Patients at risk for methemoglobinemia should not use EMLA. These include patients with congenital or idiopathic methemoglobinemia and infants under the age of 12 months taking any methemoglobin-inducing agent125 (Box 58.4). Methemoglobinemia either resolves spontaneously or in severe symptomatic cases can be hastened by IV administration of methylene blue. Other Systemic Effects. As with injectable lidocaine, the potential risk for systemic toxicity caused by absorption of lidocaine or prilocaine is theoretically possible, but quite unlikely. Pregnancy and Lactation. The safety of topical anesthesia in pregnant or nursing women is largely unknown, as conducting studies in this population is limited by ethical constraints. In nonpregnant women, the serum levels of high concentrations of

• BOX 58.3

Eutectic Lidocaine and Prilocaine Indications and Contraindications

US Food and Drug Administration-Approved Dermatologic Indications Topical analgesia for intact skin before surgery125,137–156 Laser surgery147–149 Debridement of leg ulcers140,150–152

Other Dermatologic Uses Mucosal analgesia Pruritus Postherpetic neuralgia153–156 Distinction between Ehlers–Danlos syndrome and simple hypermobility Hyperhidrosis

Contraindications Absolute Hypersensitivity to lidocaine or prilocaine anesthetics Congenital or idiopathic methemoglobinemia Infants under 1 year of age receiving medications which induce methemoglobinemia (sulfonamides, nitrogylcerin, acetaminophen, nitroprusside, phenytoin)

Relative Mucosal application Application to broken skin Hypersensitivity to ester or other (non-lidocaine, non-prilocaine) amide anesthetics G6PD deficiency Significant cardiac disease Significant hepatic disease Use with class I antiarrhythmics (tocainide, mexiletine) Pregnancy Age 10

10

100

4

7–12 years

>20

20

200

4

644

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Injectable and Mucosal Routes of Drug Administration

Other Topical Anesthetics—Pramoxine and Dibucaine Pramoxine is a topical ether local anesthetic commonly used as a topical antipruritic agent. Dibucaine is a topical amide local anesthetic commonly used in hemorrhoidal preparations. Table 58.7 lists further information regarding topical local anesthetic agents.

Coinjectable Vasoconstrictors Epinephrine Epinephrine is most often used in dermatology as a vasoconstrictor injected with a local anesthetic. Q58.16 It has four main purposes: 1. To prolong the effect of the local anesthetic; 2. To reduce systemic absorption of the local anesthetic; 3. To aid in hemostasis; 4. To decrease the volume of the local anesthetic injected. Although other vasoconstrictors, such as phenylephrine and norepinephrine, have been used for these same purposes, epinephrine is the most common vasoconstrictor in use today. Pharmacology

Epinephrine (β-[3,4-dihydroxyphenyl]-α-methylaminoethanol) is an endogenous catecholamine that is produced by the adrenal medulla. It is synthesized in the body from the amino acid tyrosine by a series of enzymatic steps. Both the endogenous form and the synthetic form are the levorotatory (L) isomer of the catecholamine, which is 15 times more active than the dextrorotatory (R) isomer.8 Although epinephrine is both an α- and a β-adrenergic agonist, it is the α-adrenergic properties that cause vasoconstriction. Epinephrine is only stable in acidic environments, which slows the onset of the local anesthetic and makes its injection painful.179 As mentioned above, these limitations are mitigated by the addition of sodium bicarbonate, which neutralizes the pH. The maximum vasoconstrictive effect of epinephrine takes place within 7 to 15 minutes,180 and the duration of action is short (approximately 60 minutes).181 Epinephrine is rapidly inactivated in tissue primarily by enzymatic transformation to metanephrine or normetanephrine.181 These substances are then conjugated in the liver. Epinephrine also undergoes direct degradation in the liver by monoamine oxidase and catechol O-methyltransferase. Once metanephrine and normetanephrine are conjugated, they are excreted in the urine in the form of sulfates and glucuronides.181 Either sequence results in the production of vanillylmandelic acid (VMA), which can be detected in the urine. Mechanism of Action. Epinephrine is an α-, β1-, and β2adrenergic agonist. Its vasoconstriction in the skin and mucous membranes is accomplished by stimulation of α-adrenergic receptors found on cutaneous vascular smooth muscle cells. Epinephrine is more effective when used with lidocaine than with bupivacaine or etidocaine, because these agents already have delayed onset of action caused by high protein binding. When used in higher concentrations for treating anaphylaxis, epinephrine’s effect on β1-adrenergic receptors increases cardiac output. The β2-adrenergic stimulation is responsible for bronchodilation, and the α-adrenergic effects increase systemic vascular resistance, thereby increasing blood pressure.

Clinical Use US Food and Drug Administration-Approved Indications.

FDA-approved dermatologic indications for epinephrine are for use as a hemostatic agent, to prolong the action of local anesthetics, and to treat acute hypersensitivity reactions181 (Box 58.5). Hemostasis. When injected with local anesthetics, epinephrine causes vasoconstriction and helps reduce bleeding in the surgical field. It should be emphasized that the hemostatic effect of epinephrine does not become maximal until 7 to 15 minutes after injection.180 Most commonly, it is prepackaged with the local anesthetic. Some authors feel that adding epinephrine to local anesthetic just before use can reduce the pain of injection owing to the higher pH of this freshly prepared solution.54 Epinephrine has also been used as a topical hemostatic agent. In harvesting split-thickness skin grafts (STSG), epinephrine combined with a water-based jelly has been used as a lubricant for the dermatome, which aids in hemostasis.182 Epinephrine in a concentration of 1:100,000 has also been combined with saline and applied with a spray bottle to STSG donor sites.183 Prolonging the Action of Local Anesthetics. As a direct result of vasoconstriction, the absorption of local anesthetics is delayed by using epinephrine.184 As evident in Table 58.2, epinephrine can more than double the duration of action of local anesthetics in the skin. In the case of lidocaine, the duration of action without epinephrine is approximately 30 to 60 minutes; with epinephrine, this is prolonged to 120 to 360 minutes. This translates into fewer injections during a relatively lengthy procedure. Another side benefit of this vasoconstriction is a reduced risk of systemic toxicity from the lidocaine. Acute Hypersensitivity Reactions. Epinephrine is also indicated for the treatment of anaphylaxis and anaphylactoid reactions such as those caused by drugs or insect stings. The dose administered in this setting is higher, 0.3 to 0.5 mg of epinephrine (1:1000) delivered subcutaneously. This dose may be repeated every 5 to 10 minutes. The treatment of anaphylaxis has been reviewed elsewhere.185,186 Adverse Effects Cardiac Effects. The effect of epinephrine on the heart of

healthy individuals is generally inconsequential, except for symptomatic palpitations. However, dysrhythmias and hypertension may occasionally occur with therapeutic doses or in the case of unrecognized overdosing.181 Patients with ischemic heart disease are more susceptible to dysrhythmias and compromised coronary blood flow, owing to the tachycardia and increased cardiac output caused by epinephrine.187 Dental surgery has supported the safety of small amounts of local infiltrative anesthesia with epinephrine (i.e., 1.8 mL to 3.6 mL of lidocaine 2% with epinephrine 1:100,000) in patients with stable cardiovascular disease, including hypertension, ischemic heart disease, arrhythmia, chronic coronary disease, and heart transplantation.188 However, safety data cannot be extrapolated to dermatologic surgery, where procedures may require much larger volumes of anesthetic solution. Primarily because of these potential cardiac effects, dosage maxima have been suggested in an attempt to minimize complications. There is no consensus regarding what dose is completely safe: it is generally recommended to use the lowest dose possible.189 However, several authors recommend a maximum of 200 mg for all patients.190,191 Others suggest a maximum dose of 200

TABLE Key Pharmacology Concepts—Commonly Used Topical Local Anesthetics 58.7

Lidocaine

EMLA

Dyclonine

Capsaicin

Dibucaine

Doxepin

Benzocaine

Pramoxine

Frequency of application

q3–4 hours

1–3 hours before procedure

q2–3 hours

3–5 times daily

q2–4 hours

4 times daily

p.r.n.

4 times daily

Onset of actiona

38ºC)

Systemic involvement

• Enlarged lymph nodes involving 2 or more sites • Involvement of one or more internal organ

• Liver abnormalities (ALT >100 U/L) or other organ involvement • Lymphadenopathy

Other

• R eaction suspected to be drug-related • Hospitalization

• Prolonged clinical symptoms 2 weeks after discontinuation of the causative drug • HHV-6 reactivation

aAt

least 3 criteria should be present for a diagnosis of DRESS. criteria includes Drug-induced Hypersensitivity Syndrome (DIHS). Typical DIHS defined as presence of all criteria and atypical DIHS is defined as all criteria except for lymphadenopathy and HHV-6 reactivation. ALT, Alanine aminotransferase; DRESS, drug reaction with eosinophilia and systemic symptoms; HHV-6, human herpesvirus 6. bJ-SCAR

Anticonvulsants Q67.2 DRESS has been commonly associated with the aromatic anticonvulsants, namely phenytoin, phenobarbital, oxcarbazepine, and carbamazepine.13,28 The nonaromatic anticonvulsant, lamotrigine, may induce DRESS as well. Several mechanisms have been implicated in DRESS syndrome, including the formation of toxic metabolites by phenytoin, carbamazepine, and phenobarbital.29,30 Human herpesvirus (HHV)-6 reactivation, well described in organ transplant recipients, has also been associated with DRESS.31,32 HHV-6 reactivation is considered to be a diagnostic criteria for the Japanese consensus group for DRESS.33 Cytomegalovirus (CMV), Epstein-Barr virus (EBV) and HHV-7

reactivation have also been implicated in a minority of cases.5,34 Viral infections may act as, or generate the production of, “danger signals” leading to damaging immune responses to drugs, rather than immune tolerance.35 Danger signals can be exogenous, endogenous, intracellular or secreted from distressed and injured cells; as well danger signals include proinflammatory cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1). Alternatively, herpesvirus reactivation in DRESS may result from an allergic immune response to a drug, with an innate ability to stimulate T cells, which may have harbored the latent herpesvirus.5,34 In one study,29 75% of a series of patients, with anticonvulsant DRESS to one aromatic anticonvulsant, showed in  vitro

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Major Adverse Effects From Systemic Drugs

• BOX 67.3 Medications Associated with Drug-

Induced Pseudolymphoma22,23,25,26 Anticonvulsants Carbamazepine Lamotrigine Phenobarbital Phenytoin Valproic acid

Other Drugs Amitriptyline Allopurinol Amlodipine Atenolol Cyclosporine Diltiazem Tamoxifen Vaccines (aluminum hydroxide containing)

cross-reactivity to the other two. Nonaromatic anticonvulsants and benzodiazepines have been well tolerated, as alternative treatments in patients with reactions to aromatic anticonvulsants.36 In addition, in vitro testing showed that there is a familial occurrence of hypersensitivity to aromatic anticonvulsants.29 Q67.2 Although lamotrigine is not an aromatic anticonvulsant, there have been several reports documenting a DRESS associated with its use as well.37

Sulfonamide Antibiotics Sulfonamide antibiotics have also been reported to cause DRESS in susceptible individuals. The primary metabolic pathway for sulfonamides involves acetylation to a nontoxic metabolite, followed by renal excretion. An alternative metabolic pathway, quantitatively more important in slow acetylators, involves the cytochrome P-450 (CYP) enzymes.38 Q67.3 These enzymes can transform the parent compound to reactive metabolites, namely hydroxylamines and nitroso compounds, that produce cytotoxicity, independent of preformed drug-specific antibody.39 In most individuals, detoxification of the metabolites occurs. Patients who are unable to detoxify this metabolite via reduction40 (e.g., glutathione-deficient patients) may be at higher risk for DRESS. The detoxification defect is present in 2% of the population, but only one in 10,000 people manifests symptoms of sulfonamide-induced DRESS. Notably, patients’ siblings and other first-degree relatives are at an increased risk (perhaps one in four) of having a similar defect. Q67.4 Other aromatic amines, such as procainamide, dapsone, and acebutolol, are metabolized to similar compounds. It may be prudent to recommend avoidance of aromatic amine drugs in patients who develop symptoms compatible with a sulfonamide DRESS because of the potential for cross-reactivity. All sulfonamide antibiotics (sodium sulfacetamide, silver sulfadiazine, sulfamethoxazole) should be avoided in patients with a history of DRESS to a sulfonamide antibiotic. Also as sulfasalazine has been shown to be cross-reactive with sulfamethoxazole, this drug should also be avoided.41 However, cross-reactivity with sulfonamides should not occur with related drugs that are not aromatic amines (e.g., sulfonylureas, thiazide diuretics, furosemide, acetazolamide).42,43 This principle, regarding lack of cross-reactivity between aromatic and nonaromatic sulfonamides, pertains to the

full spectrum of cutaneous reactions to sulfonamide antibiotics, including DRESS.

Dapsone There are several reports of dapsone-induced DRESS, also known as the sulfone syndrome or dapsone syndrome,44 in patients with a variety of dermatologic conditions, including leprosy, dermatitis herpetiformis, acne vulgaris, psoriasis, and lupus erythematosus. Dapsone-induced DRESS usually occurs 4 or more weeks after initiation of therapy and is typified by fever, rash, and hepatitis. Infiltrative lung disease is also commonly seen in patients with dapsone-induced DRESS.45 Q67.3 Dapsone is metabolized primarily via two pathways: N-acetylation and N-hydroxylation. N-acetylation is mediated by N-acetyltransferase type 2, whereas N-hydroxylation is mediated primarily by CYP3A4. Reactive intermediate metabolites (hydroxylamine metabolites) produced by N-hydroxylation are formed, which can induce hemolytic anemia and methemoglobinemia. In addition, these reactive metabolites are involved in the pathogenesis of dapsone-induced DRESS.44 Cimetidine, an inhibitor of CYP3A4, has been shown to reduce the formation of the toxic hydroxylamine metabolites of dapsone in vitro, but does not affect acetylation of dapsone.33 Subsequent studies showed that long-term (at least 3 months) concurrent cimetidine use results in increased plasma dapsone levels, without an increase in hemolysis, with reduced methemoglobinemia and no change in efficacy.46 Whether concurrent use of dapsone and cimetidine also reduces the incidence of dapsone-induced DRESS is unknown. In addition, associations between human leucocyte antigen (HLA)B*1301 and dapsone-induced cutaneous reactions have been identified; some clinicians have suggested that screening for HLAB*1301, before initiation of dapsone therapy, may be warranted in Asian populations.47

Minocycline DRESS has also been associated with minocycline,3 usually occurring 2 to 4 weeks after therapy is started. There have been several cases of myocarditis associated with minocycline-induced DRESS.48,49 Although most cases of minocycline DRESS resolve promptly,50 there are several reports in the literature of patients with prolonged courses after drug cessation, lasting up to several months.51,52 A persistence of minocycline in the plasma and/or in the skin was shown in seven out of nine patients with skin phototypes V and VI. In these patients, the levels were persistent 11 days, to as long as 17 months, after discontinuation of the minocycline.51 Multiple autoimmune sequelae (thyroid disease, type 1 diabetes mellitus and elevated markers of systemic autoimmunity) have been documented in association with minocycline-induced DRESS.18 Minocycline has also been associated with the development of chronic/autoimmune hepatitis.19,53 Q67.5 The pathogenesis of minocycline-induced DRESS is unknown; however, minocycline metabolism may generate a reactive iminoquinone derivative. Neither tetracycline nor doxycycline contains the amino acid side chain that has the potential to form this reactive metabolite; this may support the medical experience that neither tetracycline nor doxycycline is associated with DRESS.37 However, certainty regarding the absence of crossreactivity between minocycline and other tetracyclines is lacking; therefore caution is advised regarding administration of other tetracyclines in patients who develop a DRESS after minocycline.

CHAPTER 67

Other Drugs Allopurinol is associated with the development of serious drug reactions, including DRESS. In a review of 60 patients with DHS, allopurinol was cited as the culprit drug in 19 cases (32%).6 A longer incubation time was noted in patients with allopurinolinduced DRESS than with phenytoin-induced DRESS (27 days vs, 14 days, respectively). Also, chronic renal impairment was a characteristic clinical feature of allopurinol-induced DRESS. In a review of 13 patients with allopurinol DRESS, fever and rash were the most common presenting symptoms. Other associated abnormalities included leukocytosis (62%), eosinophilia (54%), renal impairment (54%), and liver dysfunction (69%).54 Active infection or reactivation of HHV-6 has been observed in patients who develop allopurinol-induced DRESS.55 Allopurinol-induced adverse reactions, including DRESS, SJS, and TEN, have been strongly associated with a genetic predisposition in Han Chinese; the HLA-B*5801 allele was found to be an important genetic risk factor.56 Nevirapine has been associated with the DRESS, involving various combinations of fever, hepatitis, and rash. Studies have suggested that HLA-DRB1*0101 and the CD4 status of a patient may determine susceptibility to nevirapine hypersensitivity.57 Vancomycin has also been associated with DRESS.58 In one series of 104 patients with symptoms of DRESS, the most commonly implicated drugs were antibiotics, followed by antiepileptics and traditional Chinese medicines. The antibiotics most frequently associated with DRESS were cefaclor, levofloxacin, amoxicillin, and cefuroxime axetil.59

Differential Diagnosis The differential diagnosis of DRESS includes other cutaneous drug reactions, acute viral infections (e.g., EBV, hepatitis virus, influenza virus, CMV), lymphoma, and idiopathic hypereosinophilic syndrome.8,12 After DRESS has been recognized by the symptom complex of fever, rash, eosinophilia (typically >1.5 x 109/L)60 and lymphadenopathy, there are a minimum number of laboratory tests (Box 67.4) that help to evaluate internal organ involvement, which may be asymptomatic. Liver transaminases, CBC, and urinalysis and serum creatinine should be performed at the initial evaluation. In addition, the clinician should be guided by the presence of symptoms, which may suggest specific internal organ involvement (e.g., respiratory symptoms). Thyroid function tests should be measured and repeated in 2 to 3 months. A skin biopsy may be helpful if the patient has a blistering or a pustular eruption. Unfortunately, there are no readily available diagnostic or confirmatory tests to establish a drug’s role in causation. An in vitro test, using a mouse hepatic microsomal system, is used for research purposes to evaluate patients who develop DRESS.61 Oral rechallenge and desensitization are not recommended because of the potential severity of the DRESS reactions.

Treatment Drug discontinuation is paramount in the management of patients with DRESS.62 Q67.6 Some clinicians elect to start prednisone at a dose of 1 to 2 mg/kg daily, if symptoms are severe (e.g., transaminase levels >5 times normal, renal involvement, and/or pneumonia),62 with a slow taper, often over weeks to months. In contrast to the controversial role of corticosteroids (CS) in SJS and TEN, there is no significant barrier function alteration leading

Cutaneous Drug Reactions With Systemic Features

747

• BOX 67.4 Management of Patients with Drug

Reaction with Eosinophilia and Systemic Symptoms 1. Discontinue the offending drug 2. Obtain the following laboratory tests: a. At presentation: • CBC with differential • Liver function tests (especially transaminases) • Urinalysis (routine and microscopic) • Serum creatinine • Other tests may be needed, depending on the symptom presentation (e.g., chest radiograph for respiratory symptoms) • Baseline thyroid function tests (e.g., TSH) b. At 1 year of age, 50 µg/kg daily for infants) while patients are taking MTX. Hepatic fibrosis is a well-documented long-term AE of MTX in adults. Several studies have failed to demonstrate significant irreversible hepatotoxicity, in children using MTX at lower (nononcologic) doses.62,63 Q70.7 Liver biopsies are very rarely recommended or required for children, especially those with cumulative doses below 1.5 g and without laboratory abnormalities. The role of ultrasound based Fibroscans in children receiving chronic MTX is yet to be defined. MTX is best avoided in pediatric patients at elevated risk for MTX-induced hepatic complications (obese, diabetic, pre-existing liver disease, taking other high-risk medications). It has long been established that long-term MTX, given at very high doses, such as used in pediatric oncology, may reduce bone density.64,65 It is less clear what the effect, if any, of relatively short-term, and lower-dose, MTX therapy is on bone mineralization in pediatric patients on monotherapy for cutaneous inflammatory diseases. Some sources recommend supplementation with vitamin D (at least 400 IU daily) and calcium (500 mg daily [children age 1–3 years ] and calcium 800 mg daily [children age 4–8 years] or 1300 mg daily (children age 9–18 years]) to help maintain overall bone density.66 In general, monitoring for MTX toxicity includes complete blood count, hepatic transaminases, and creatinine, although there is no consensus regarding a particular monitoring protocol. Monitoring for latent infections, such as tuberculosis and hepatitis or human immunodeficiency virus, should be considered before and during therapy based on individual circumstances and geographic location. MTX should be avoided in the settings of pregnancy and liver dysfunction, and dose adjustments should be made for renal dysfunction. Bone marrow toxicity may be increased by medications that interfere with the folate metabolic pathway (such as TMP/SMX) and nonsteroidal anti-inflammatory drugs, which may decrease the renal clearance of MTX.

Azathioprine AZA is a purine analog, whose immunosuppressive action is thought to derive from inhibition of DNA production in rapidly proliferating B and T cells during inflammation. AZA is used offlabel to treat severe cutaneous inflammatory disorders in children, including AD,67,68 various forms of cutaneous lupus, and refractory morphea among other conditions. Dosing Considerations for Children. AZA dosing is in the range of 1 to 3 mg/kg/day, but occasionally higher doses (up to 4 mg/kg/day) may be required for optimal effect. In children, 2.5 mg/kg/day is a most common average dose, and the most effective dose range is probably between 2.5 and 3.5 mg/kg/day. GI intolerance (nausea, abdominal cramping) is a limiting factor in dose optimization. Graduated dosing (start with lower initial doses followed by slow escalation) may reduce the severity of early GI AE. Q70.8 Baseline thiopurine methyltransferase (TPMT) levels should be used to guide initial dosing and subsequent dose

adjustments if the disease is not responding as expected, as TPMT is an inducible enzyme whose levels may change over time. Dosing guided by TPMT levels can reduce the risk of clinically significant myelosuppression, a well-documented risk of AZA use, especially in the setting of TPMT deficiency, but TPMT activity does not necessarily predict therapeutic response nor the risk of hypersensitivity reactions (fever, malaise, myalgias, rash) to AZA. Adverse Effects and Monitoring. Short-term AE of AZA are primarily GI (nausea, vomiting, abdominal pain, bloating, anorexia) and are the most common reason for drug discontinuation. Headache, hypersensitivity reactions (fever, myalgia, rash), deranged liver enzymes, and leukopenia have been variably reported and close clinical and laboratory monitoring is recommended before and throughout therapy. In nondermatologic patient populations, especially patients on multiple immunosuppressants, there is an increased risk of infections (mainly viral), lymphoma, and nonmelanoma skin cancer. Insufficient long-term data exist to generalize these findings to the pediatric dermatology (primarily AD) population, treated with AZA as monotherapy. That said, AZA is often a second-line choice of therapy reserved for severe refractory skin disease given the inability to fully resolve concerns regarding potential increased long-term risk of malignancy.69 (See Chapter 14 for a more detailed AE profile).

Cyclosporine CSA is an oral immunosuppressant that exerts its action by binding to cyclophilin, forming a complex that inhibits calcineurin, thereby inhibiting the production of interleukin (IL)-2. Inhibition of IL-2 prevents the activation of both T-helper and T-regulatory cells. CSA has been found to be effective in both children and adults with severe AD and various forms of psoriasis. Because its long-term use is limited by the risk of renal toxicity, hypertension, and immunosuppression, CSA is often used to gain rapid control of the disease followed by transition to a longer-term medication. Dosing Considerations for Children. CSA is typically dosed between 2 and 5 mg/kg/day in children of all ages. It is available in 25 mg and 100 mg capsules and 100 mg/mL oral solution. Oral bioavailability may be less in children compared with adults, whereas clearance may be faster; therefore children may require higher doses by weight than adults to achieve efficacy. Dose adjustments are made based on clinical response, serum creatinine levels, and blood pressure. CSA is fast-acting. Improvement in inflammatory skin disease, such as AD and psoriasis, may be observed within 1 to 2 weeks, although full effect is often observed between 4 and 8 weeks after initiation. One common approach to reduce toxicity is to gain control of the disease, maintain control for a month or 2, then begin gradual tapering to lowest effective dose with a plan to transition off or to another agent as necessary. Adverse Effects and Monitoring. Renal toxicity and hypertension are potential AE of long-term CSA use. Its use is typically limited to 1 year of continuous treatment in the United States (and 2 years in Europe). Pediatric trials indicate that renal toxicity and hypertension may be rarer in children than in adults.68,70,71 Serious infections in the setting of monotherapy for skin disease are possible but rare. Commonly reported short-term AE include headaches and GI upset. Risks associated with high-dose CSA used in the context of multidrug organ transplantation regimens, such as hypertrichosis, paresthesias, arthralgias, and gingival hyperplasia, seem less common in children treated for skin disease.72 Lymphoproliferative malignancies observed in the transplant population have not been observed in children on shortterm, low-dose monotherapy.

CHAPTER 70

Before and during treatment with CSA, evaluation of complete blood count, serum electrolytes, creatinine, urea, cholesterol, triglycerides, blood chemistries and blood pressure is advisable. Administration of live virus vaccines is contraindicated during CSA treatment.

Biologic Therapies Biologic therapies (mechanisms, dosing, AE, and monitoring) are covered in detail elsewhere in this book. The following comments refer to treatment approaches for children. Targeted therapies have become part of the first-line choice of therapeutics for pediatric patients with severe psoriasis, and increasingly, atopic dermatitis. Q70.9 Evidence supporting the safety and efficacy of these therapies has resulted in FDA approval of etanercept, an antitumor necrosis factor alpha (TNF-α) agent, and ustekinumab, an anti-IL 12/23 therapy, for moderate to severe pediatric psoriasis. The anti-IL 4/13 medication, dupilumab, has very recently been approved for atopic dermatitis, in patients 12 years of age and older. See chapter 31 for complete details on dupilumab including use in adolescents with AD. Data on the efficacy of newer mechanisms for pediatric patients, such as antiIL17 and phosphodiesterase 4 (PDE-4) inhibitors for psoriasis, continue to emerge, although currently these latter mechanisms lack FDA approval in the pediatric population. Biologic agents have the advantage of less frequent dosing, far less frequent laboratory monitoring, and to date, seem to lack the potential end-organ toxicities, associated with conventional systemic therapies.73 Challenges to using biologic therapy for children are the need for injections, the very high cost, and lack of regulatory agency approval of some agents, which often results in rejection of insurance approval. The decision to prescribe a biologic therapy for children with psoriasis, AD, or other clinical indications should be individualized, based on the clinical situation and this decision ideally should be made together with the patient and family (“shared decision making”). Baseline and ongoing laboratory monitoring for biologic therapies should include frequent assessments for signs and symptoms of infection and injection site reactions. Additional monitoring should be per the drug label and individualized to the specific clinical scenario. Immunizations should be updated for the patient and for household contacts before starting biologic therapy. During treatment, live and liveattenuated vaccines should be avoided.

Tumor Necrosis Factor Inhibitors in Children Three main TNF-α inhibitor—infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira)—are prescribed to children with psoriasis and/or psoriatic arthritis. Etanercept is FDA-approved in the United States for children with moderate to severe psoriasis aged 4 years and older and has accumulated the most efficacy and long-term safety data in pediatric psoriasis. Neither infliximab nor adalimumab are currently licensed for children in the United States (adalimumab is licensed in the European Union for psoriasis in children aged 12 years and older) but are used nonetheless. Adverse Effects and Monitoring. (See Chapter 26 for a complete discussion of TNF AE.) Infectious complications (both common and opportunistic infections) and injection or infusion site reactions are the most common AE of anti-TNF therapy in children. The risk of demyelinating diseases from TNF-α inhibitor therapy is theoretically worrisome but has not been reported, as far as we know, in pediatric patients on anti-TNF monotherapy for

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psoriasis to date. There are also theoretical concerns about increased risk of malignancies, particularly lymphomas. In April 2009 the FDA published a warning related to TNF-α blockers. Approximately 48 malignancies were reported in children and adolescents, of which about half were lymphomas. A higher rate of malignancy was observed in patients treated with infliximab and etanercept. An important caveat of this, however, is that the vast majority of these patients were also on concurrent therapy with other immunosuppressive agents, including MTX and AZA. The development of psoriasiform eruptions in children, with IBD during treatment with TNF inhibitors, has become well-recognized.74,75

Etanercept Etanercept is a TNF receptor-immunoglobulin (Ig)G fusion molecule that inhibits soluble and membrane-bound TNF-α and TNFβ. It is administered as a weekly subcutaneous injection of 0.8 mg/ kg/dose (max 50 mg). Etanercept has amassed the largest body of safety and efficacy evidence and communal experience, and at the time of this writing, it is the only anti-TNF agent approved by the FDA for pediatric psoriasis (aged ≥4 years).76 The most common AE reported in long-term surveillance (264 weeks) of pediatric psoriasis patients were upper respiratory infections, injection site reactions, and headaches; there was only one serious AE that was considered treatment related, a case of cellulitis. No opportunistic infections or malignancies were reported.77

Adalimumab Adalimumab is a fully humanized monoclonal antibody that targets TNF-α. It is administered as subcutaneous injections, dosed at 24 mg/m2 or 0.8 mg/kg weekly (maximum 40 mg), for the first 2 weeks and then every 2 weeks. Adalimumab was approved in 2008 for juvenile inflammatory arthritis (JIA) in children ages 4 years and above, and in 2015 it was approved in the European Union for psoriasis in children aged 4 years and above. It is also FDA approved for the treatment adult psoriasis and psoriatic arthritis. Its use in pediatric psoriasis remains off-label but approval is anticipated in the near future. Adalimumab has the advantage of less frequent dosing compared with etanercept and has been shown to be effective in unique and challenging clinical circumstances, including pediatric generalized pustular psoriasis and nail psoriasis. In a large pediatric trial comparing adalimumab to MTX, adalimumab was well tolerated, with infection the most frequently reported AE followed by rare injection site reactions. There were no reported opportunistic infections, malignancies or deaths.78

Infliximab Infliximab is a chimeric monoclonal antibody with high affinity for both soluble and transmembrane TNF-α. It was approved by the FDA for psoriatic arthritis in adults in 2005, for severe chronic plaque psoriasis in adults 2006, and in 2006 for Crohn disease, in children aged 6 years and older. It is often used off-label for severe inflammatory diseases in children, including psoriasis, graft-versus-host disease, Kawasaki disease, morphea, SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome, and hidradentitis.79–81 Infliximab is administered as intravenous infusions of 3.3 to 5 mg/kg/dose at weeks 0, 2, 6, and then every 7 to 8 weeks, thereafter. Infliximab has the advantage of rapid onset of action, even within hours to days, which makes it a good

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choice for acute generalized pustular and erythrodermic psoriasis. Its monitored administration assures compliance. Development of antimurine antibodies may limit its efficacy over time and increase the risk of infusion reactions. In addition to the most common reported AE, upper respiratory infections, pharyngitis and infusion reactions, patients treated with infliximab may experience hepatotoxicity (acute liver failure, jaundice, cholestasis, hepatitis, and autoimmune hepatitis), systemic vasculitis, serum sicknesslike reactions and seizures. Anti–IL-12/23 Therapy. Ustekinumab is a fully human IL-12 and IL-23 antagonist, FDA approved in October, 2017, for the treatment of moderate to severe plaque psoriasis, in adolescents aged 12 years and older. It is administered subcutaneously as 0.75 mg/kg at weeks 0 and 4 and then every 12 weeks after that. Ustekinumab is particularly attractive for use in pediatrics because of its rapid onset of action, excellent efficacy, and convenient dosing schedule. The CADMUS (A Study of the Safety and Efficacy of Ustekinumab in Adolescent Patients With Psoriasis) study demonstrated 80% Psoriasis Area and Severity Index (PASI)-75 and 61% PASI-90 at 12 weeks of therapy, in this population.82 An ongoing study is evaluating the efficacy and safety of ustekinumab in ages 6 to 12 years (CADMUS Jr).83 In studies evaluating adolescent psoriasis patients undergoing ustekinumab treatment the most common AE were minor respiratory infections. There were no anaphylactic reactions, serum-sickness like reactions, malignancies or active tuberculosis cases through the 60 weeks of the study.82 Other potential risks include allergic reactions manifesting as angioedema and anaphylaxis, and reversible posterior leukoencephalopathy syndrome. Nonmelanoma skin cancers have been reported in older adult patients (especially >60 years) and those with a history of prolonged immunosuppression or psoralen and ultraviolet A (PUVA) therapy. Precaution should be used in pediatric patients who are at increased risk for nonmelanoma skin cancer. Patients should be screened at baseline and annually for tuberculosis and if applicable, should be treated before initiation of ustekinumab therapy. There are no other specific monitoring guidelines, and additional screening should be individualized. As with other biologics, immunizations should be updated before initiation of therapy for patients and household contacts. Live attenuated vaccines should be avoided during therapy, and vaccination with Bacillus-Calmette-Guerin (BCG) should be avoided for 1 year before, during and 1 year after ustekinumab therapy.

Acknowledgement The authors would like to thank Brandie Styron for her contribution to the prior version of this chapter.

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56. Barnes CJ, Eichenfield LF, Lee J, Cunningham BB. A practical approach for the use of oral isotretinoin for infantile acne. Pediatr Dermatol. 2005;22:166–169. Acitretin 57. Marqueling AL, Cordoro KM. Systemic treatments for severe pediatric psoriasis: a practical approach. Dermatol Clin. 2013;31(2):267–288. 58. Lacour M, Mehta-Nikhar B, Atherton DJ, Harper JI. An appraisal of acitretin therapy in children with inherited disorders of keratinization. Br J Dermatol. 1996;134(6):1023–1029. 59. Van Zander J, Orlow SJ. Efficacy and safety of oral retinoids in psoriasis. Expert Opin Drug Saf. 2005;4(1):129–138. 60. GSK. Soriatane (acitretin) capsules [prescribing information]. Revised September 2017. Available at: https://www.gsksource. com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Soriatane/pdf/SORIATANE-PI-MG.PDF. Accessed April 11, 2019. Methotrexate 61. Silvergate Pharmaceuticals. Xatmep (methotrexate) oral solution [prescribing information]. Revised December 2018. Available at: http://xatmep.com/Xatmep-Prescribing-Info.pdf. Accessed April 11, 2019. 62. Graham LD, Myones BL, Rivas-Chacon RF, Pachman LM. Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. J Pediatr. 1992;120(3):468–473. 63. Rose CD, Singsen BH, Eichenfield AH, Goldsmith DP, Athreya BH. Safety and efficacy of methotrexate therapy for juvenile rheumatoid arthritis. J Pediatr. 1990;117(4):653–659. 64. Ragab AH, Frech RS, Vietti TJ. Osteoporotic fractures secondary to methotrexate therapy of acute leukemia in remission. Cancer. 1970;25(3):580–585. 65. Schwartz AM, Leonidas JC. Methotrexate osteopathy. Skeletal Radiol. 1984;11(1):13–16. 66. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Drug and therapeutics committee of the lawson Wilkins pediatric endocrine society. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122(2):398–417. Azathioprine 67. Murphy LA, Atherton D. A retrospective evaluation of azathioprine in severe childhood atopic eczema using thiopurine methyltransferase levels to exclude patients at high risk of myelosuppression. Br J Dermatol. 2002;147(2):308–315. 68. Ricci G, Dondi A, Patrizi A, Masi M. Systemic therapy of atopic dermatitis in children. Drugs. 2009;69(3):297–306. 69. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71(2):327–349. Cyclosporine 70. Shaw MG, Burkhart CN, Morrell DS. Systemic therapies for pediatric atopic dermatitis: a review for the primary care physician. Pediatr Ann. 2009;38(7):380–387. 71. Bunikowski R, Staab D, Kussebi F, et  al. Low dose cyclosporine A microemulsion in children with severe atopic dermatitis: clinical and immunological effects. Pediatr Allergy Immunol. 2001;12(4):216–223. 72. Pereira TM, Vieira AP, Fernandes JC, Sousa-Basto A. Cyclosporin A treatment in severe childhood psoriasis. J Eur Acad Dermatol Venereol. 2006;20(6):651–656.

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Biologic Therapies 73. Bronckers IMGJ, Seyger MMB, West DP, et  al. Safety of systemic agents for the treatment of pediatric psoriasis. JAMA Dermatol. 2017;153(11):1147–1157. Tnf-Α Inhibitors 74. Manni E, Barachini P. Psoriasis induced by infliximab in a patient suffering from Crohn’s disease. Int J Immunopathol Pharmacol. 2009;22(3):841–844. 75. Collamer AN, Battafarano DF. Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: clinical features and possible immunopathogenesis. Semin Arthritis Rheum. 2010;40(3):233–240. 76. Paller AS, Siegried EC, Langley RG, et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med. 2008;358(3):241–251. 77. Paller AS, Siegfried EC, Pariser DM, et al. Long-term safety and efficacy of etanercept in children and adolescents with plaque psoriasis. J Am Acad Dermatol. 2016;74(2): 280–287.e1–e3. Adalimumab 78. Papp K, Thaçi D, Marcoux D, et  al. Efficacy and safety of adalimumab every other week versus methotrexate once weekly in children and adolescents with severe chronic plaque

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psoriasis: a randomised, double-blind, phase 3 trial. Lancet. 2017;390(10089):40–49. Infliximab 79. Haslund P, Lee RA, Jemec GB. Treatment of hidradenitis suppurativa with tumour necrosis factor-alpha inhibitors. Acta Derm Venereol. 2009;89(6):595–600. 80. Diab M, Coloe JR, Magro C, Bechtel MA. Treatment of recalcitrant morphea with infliximab. Arch Dermatol. 2010;146(6):601–604. 81. Ben Abdelghani K, Dran DG, Gottenberg JE, Morel J, Sibilia J, Combe B. Tumor necrosis factor-alpha blockers in SAPHO syndrome. J Rheumatol. 2010;37(8):1699–1704. Anti–Il-12/23 Therapy 82. Landells I, Marano C, Hsu MC, et al. Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: results of the randomized phase 3 CADMUS study. J Am Acad Dermatol. 2015;73(4):594–603. 83. A phase 3 open-label study to assess the efficacy, safety, and pharmacokinetics of subcutaneously administered ustekinumab in the treatment of moderate to severe chronic plaque psoriasis in pediatric subjects greater than or equal to 6 to less than 12 years of age. ClinicalTrials.gov Identifier: NCT02698475. Updated March 28, 2019.

Appendix

I

Core Questions for Understanding Systemic Dermatologic Drugs Section 1—Pharmacology basic science Section 2—Clinical use Section 3—Severe adverse effects Section 4—Less serious adverse effects Section 5—Drug safety monitoring Section 6—Drug interactions (see also Appendix 2) Section 7—Miscellaneous issues

Section 1—Pharmacology Basic Science Q1.1 What are the simplest definitions of ‘pharmacokinetics’, ‘pharmacodynamics’, and ‘pharmacogenetics’? (Pg. 1, Table 1.1) Q1.3 What are some of the pros and cons to the decision of whether to calculate drug dose on (1) actual body weight, (2) ideal body weight? (Pg. 3) Q1.6 What are several of the most important examples in which drugs inhibit specific enzymes? (Pg. 6, Table 1.6) Q1.7 What are several important examples of active drug and active metabolite relationships? (Pg. 7, Table 1.9) Q1.8 What are several of the most important examples of pro­ drug and active drug relationships? (Pg. 8, Table 1.8) Q1.10 What are five of the most important basic components that determine percutaneous absorption of topical medications in general? (Pg. 8) Q9.2 Which antibiotic classes have significant alterations in bio­ availability because of foods and divalent cations? (Pgs. 73, 75, 78, 81, 82, 84x2, 91, 92) Q9.5 What are three to four of the mechanisms by which bacteria develop resistance to antibacterial agents? (Pgs. 78, 84, 91, 95, 96) Q9.8 What are several antibiotic classes with significant anti­ inflammatory activity, and what are several of the mechanisms for this anti­inflammatory activity? (Pgs. 78, 83x2) Q10.3 How do the pharmacokinetics of terbinafine, itracon­ azole, and fluconazole in (1) the sweat, sebum, and stratum corneum, (2) the nails, and (3) the hair influence the option of intermittent/pulse therapy? (Pg. 102x3) Q10.5 Considering the allylamine mechanism (terbinafine), (1) what enzyme is inhibited, (2) what conversion step is inhib­ ited, and (3) is the net in vitro result fungicidal or fungistatic? (Pg. 103) Q10.6 Considering the azole mechanism (itraconazole, flucon­ azole), (1) what enzyme is inhibited, (2) what conversion step is inhibited, and (3) is the net in vitro result fungicidal or fun­ gistatic? (Pg. 103) Q11.2 What are the two primary steps (one step with two parts) by which acyclovir reaches the form that inhibits viral replication

(similar steps for valacyclovir and famciclovir) (Pg. 115, Fig. 11.2) Q11.5 Of the three drugs for HHV infections discussed in this chapter, which two are defined as ‘prodrugs’ for another active drug? (Pgs. 119, 121) Q11.7 How does the bioavailability differ between acyclovir, va­ lacyclovir, and famciclovir? How might this relate to treating varicella­zoster virus (VZV) infections and herpes simplex vi­ rus (HSV) infections?) (Pg. 121) Q13.1 Concerning prednisone and cortisone, what is (1) the ac­ tive form of each drug, and (2) the enzyme necessary for this conversion, and (3) the effect of severe liver disease on this con­ version? (Pgs. 134, 135) Q13.2 What are ‘physiologic dose’ levels for (1) prednisone, (2) prednisolone, (3) dexamethasone, (4) methylprednisolone, and (5) triamcinolone? (Table 13.1, Pg. 151) Q13.9 Concerning response to physical stressors, which part of the hypothalamic­pituitary­adrenal (HPA) axis is (1) quickest to be suppressed, (2) quickest to recover, and (3) overall most important to stress responsiveness? (Pg. 148) Q13.10 What are some of the ‘back­up’ mechanisms the body has to minimize the likelihood of CS­induced HPA­axis sup­ pression? (Pg. 149x2) Q14.1 What are the proposed mechanisms by which methotrex­ ate inhibits inflammatory dermatoses? (Pg. 159x4) Q14.2 What is the biochemical rationale behind the use of (1) folinic acid, and/or (2) thymidine in patients with acute methotrexate liver toxicity (especially pancytopenia)? (Pg. 159) Q15.2 What is a general guide for interpretation of the labora­ tory testing for the genotype for TPMT activity? (Pg. 170) Q16.1 How do MMF and mycophenolic acid (MPA) relate pharmacologically: (1) prodrug/active drug, or (2) active drug/ active metabolite? (Pg. 178) Q16.5 Concerning the MPA mechanism of action (1) what pu­ rine biosynthesis enzyme is inhibited, and (2) why are activated lymphocytes specifically targeted by MPA? (Pg. 179) Q17.1 What are the differences between the Sandimmune and Neoral versions of cyclosporine (CsA) in their (1) formula­ tion, (2) bioavailability, and (3) consistency of absorption? (Pgs. 187, 188, 195) Q17.2 Regarding the mechanism of action for CsA, what is (1) the enzyme inhibited, (2) the transcription factor inhib­ ited, and (3) the resultant cytokine alterations? (Pg. 188, Table 17.3, Fig 17.2) Q18.1 What are the most important differences between small molecule drugs (such as apremilast and tofacitinib) and biolog­ ics? (Pg. 200) 777

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APPENDIX 1

Core Questions for Understanding Systemic Dermatologic Drugs

Q19.2 What are (1) the two major categories of cytotoxic agents, (2) major drug examples of each category, and (3) the mecha­ nism for each category concerning the cell cycle? (Pgs. 210, 211, 214) Q20.2 What is the overall function of the myeloperoxidase sys­ tem in neutrophils? (Pg. 225) Q21.1 What are the proposed mechanisms by which antimalarials work in various dermatoses discussed in this chapter? (Pg. 236) Q22.2 How much time is needed for complete serum elimina­ tion of (1) isotretinoin, (2) acitretin, and (3) bexarotene; what is the role of acitretin re­esterification to etretinate in this issue? (Pgs. 248x2, 254) Q24.3 What are the proposed mechanisms by which ECP may benefit patients with cutaneous T­cell lymphoma (CTCL)? (Pg. 273) Q25.2 Concerning biochemistry of ALA/MAL, what (1) is the endpoint of this metabolism, (2) is the photosensitizing por­ phyrin that accumulates, and (3) what are the differences be­ tween ALA and MAL metabolism? (Pg. 281) Q25.5 Concerning the mechanism of action for ALA and MAL, what are (1) the wavelengths with peak absorption of each product, and (2) the subsequent photochemical and photobio­ logic reactions? (Pg. 282x2) Q26.1 What is the rationale strongly supporting the role of TNF­α in the pathogenesis of psoriasis? (Pg. 288) Q28.1 What is the rationale strongly supporting the role of in­ terleukin [IL]­17 in the pathogenesis of psoriasis? (Pg. 312) Q28.2 What is the rationale strongly supporting the role of IL­ 17 in the pathogenesis of psoriatic arthritis? (Pg. 313) Q28.6 How does the mechanism of action differ for brodalumab compared with secukinumab and ixekizumab? (Pg. 317) Q29.2 What subunit of IL­23 do IL­23 inhibitors target? (Pg. 321) Q30.3 Concerning B­cell depletion with rituximab, what is (1) the timing of onset, (2) the average duration of depletion and (3) the timing of recovery? Why are plasma cells spared? (Pg. 331) Q30.7 In addition to depleting pathogenic B cells, what are two ways rituximab indirectly modifies B and T autoimmunity in pemphigus? (Pg. 333x2) Q31.4 What is the mechanism of action of dupilumab that al­ lows for blockade of both interleukin (IL)­4 and IL­13 signal­ ing? (Pg. 340) Q31.9 After omalizumab binds free IgE, what are five subsequent mechanisms of action? (Pg. 343) Q32.1 How do first­ and second­generation antihistamines differ regarding lipophilic properties and anticholinergic effects, and what are the resultant clinical difference? (Pgs. 350, 352) Q32.3 Concerning chronic urticaria patients, (1) in what per­ centage are autoantibodies produced, and (2) what two types of autoantibodies are typical of this subgroup? (Pg. 350) Q32.4 How do H1 and H2 receptors differ regarding their role in (1) itching, (2) vasodilation, (3) increased vascular perme­ ability, and (4) suppression of T lymphocytes? (Pgs. 350, 351) Q32.7 What pharmacologic property allows persistence of a therapeutic effect from antihistamines significantly longer than the plasma half­life of a given antihistamine? (Pg. 352) Q32.10 Which histamine receptors do cimetidine and doxepin inhibit and how do these properties compare with traditional first­generation antihistamines? (Pgs. 355, 356) Q33.7 Why does aspirin have a paradoxically greater antiplatelet effect at relatively low doses? (Pg. 362)

Q33.8 What are the mechanisms by which pentoxifylline im­ proves various disorders of cutaneous vasculature? (Pg. 364) Q34.1 What is the difference between an ‘antiandrogen’ and ‘an­ drogen inhibitor’? (Pg. 367) Q34.4 Concerning spironolactone (1) what are the primary bio­ logic effects, and (2) what is the metabolite that contributes to the majority of the drug’s effects (Pg. 369, 371) Q36.1 What are the mechanisms by which intravenous im­ munoglobulin (IVIg) affects (1) antibody (Ab) production, (2) Ab neutralization, (3) the complement system, (4) T­cell activation, (5) immune cell trafficking, and (6) Fas/Fas ligand interaction? (Pg. 398) Q37.8 What is the mechanism of action for the following drugs: vorinostat, denileukin diftitox, ipilimumab, and etoposide? (Pg. 414, 415x2, 417) Q40.3 What are some of the properties of biotin which led to its clinical use for hair and nail disorders? (Pg. 447) Q40.5 What is the mechanism of action for colchicine, and how does this mechanism and other drug properties make the drug well suited for neutrophilic dermatoses? (Pg. 450) Q40.12 Which cytokines of central importance to inflammation do thalidomide inhibit? (Pg. 458) Q62.4 What are some of the enzymes involved with the phase I (primarily oxidation) and phase II (conjugation) metabolic steps of drug biotransformation (and which enzymes have polymorphisms)? (Pg. 679, Table 62.2) Q62.5 What are several of the mechanisms involved in the pathogenesis of drug­induced liver injury (DILI) are caused by reactive metabolic intermediates? (Pg. 680, Box 62.3) Q64.3 What are the primary components of the multistep carcinogenesis model, and what are some applications of this model for chemical, ultraviolet, and viral carcinogen­ esis? (Pg. 703) Q64.5 In general, what are the roles of oncogenes and tumor suppressor genes in carcinogenesis? (Pg. 703) Q64.6 Of the four malignancies with the highest relative risk in organ transplantation settings, which viruses are frequently co­ factors for each malignancy? (Pg. 704) Q65.5 At which stage of pregnancy does organogenesis occur, leading to the highest risk of teratogenicity? (Pg. 712) Q66.4 Which two cytochrome P­450 (CYP) isoforms are respon­ sible for the greatest amount of drug metabolism (and what are 3–4 other CYP isoforms that also account for the majority of drug interactions)? (Pg. 731) Q66.5 Which drugs are CYP3A4 inducers? (Pg. 733) Q66.9 Given the CYP2D6 polymorphism, what are four general terms and abbreviations for different overall rates of drug me­ tabolism? (Pgs. 738x2, 741) Q66.11 In addition to CYP2D6, which other CYP isoforms have a genetic polymorphism? (Pgs. 738, 739)

Section 2—Clinical Use Q9.13 What are some practice guidelines for use of systemic an­ tibiotics in chronic inflammatory dermatoses to reduce antimi­ crobial resistance? (Pg. 84) Q9.16 Concerning community­acquired methicillin­resistant Staphylococcus aureus (CA­MRSA) infections, what are (1) several of the best oral antibiotic choices, and (2) several antibiotics with a trend towards increasing resistance? (Pgs. 91x2, 94, 96, 97x4)

APPENDIX 1 Core Questions for Understanding Systemic Dermatologic Drugs

Q10.7 Considering all five main systemic antifungal agents in this chapter, which have the most optimal coverage against (1) Candida infections, (2) dermatophytes, (3) non­derma­ tophyte mold infections, and (4) Pityrosporum infections? (Pgs. 103, 105, 106) Q10.8 Why did terbinafine and itraconazole largely replace griseofulvin as treatment for dermatophyte onychomycosis? (Pg. 105) Q11.1 What is the spectrum of dermatologic conditions that human herpes virus (HHV) infections can cause? (Pg. 115, Table 11.1) Q11.4 What is the rationale for the use of acyclovir or valacyclo­ vir in patients with recurrent erythema multiforme, and which regimens are most effective? (Pgs. 118, 120) Q11.6 What advantages does valacyclovir have over acyclovir in treating herpes zoster? (Pgs. 119, 120) Q11.10 What are the two available vaccines to prevent shingles and how are they different? (Pg. 123) Q12.1 Concerning ivermectin therapy for scabies, (1) how does ivermectin compare with topical permethrin in success rate, and (2) is ivermectin alone effective treatment for crusted sca­ bies? (Pg. 126x2, 127) Q12.4 Should ivermectin be utilized differently in immunocom­ promised patients, including human immunodeficiency virus patients? (Pg. 127) Q12.7 What are the clinical implications of increasing parasite resistance to ivermectin in treating (1) onchocerciasis, and (2) scabies? (Pg. 128) Q13.3 What are several cells that systemic corticosteroid (CS) can induce to undergo apoptosis, and the disease states that may logically be successfully treated because of this apoptosis? (Table 13.2, Pgs. 136, 139x2) Q13.5 What are several pros and cons of intramuscular (IM) CS injections versus oral dosing? What are several dermatoses for which IM Kenalog has the best risk:benefit ratio and overall logic of use? (Table 13.5, Box 13.4, Pg. 141) Q13.6 What are the two key issues that determine the rapidity of systemic CS dose tapering? Which of these two key issues mat­ ters primarily when dosing is below ‘physiologic’ dose levels? (Box 13.8, Box 13.9, Table 13.14, Pgs. 142, 149, 151x2) Q13.11 What are some general principles (1) to maximize CS safety (z), (2) to taper CS therapy (Box 13.9), and (3) to convert CS to alternate­day dosing (Table 13.14)? What two criteria should be met before making this conversation? (Pgs. 51, 154x2) Q14.4 What are four to five dermatoses for which there is rea­ sonable data concerning safety and efficacy regarding use of methotrexate in children? (Pg. 162, Box 14.1) Q14.12 What are the pros and cons of the two common methods of administering weekly dosages of methotrexate, administered ei­ ther as a single dose or in divided doses over 24 hours? (Pg. 167) Q15.4 Based on TPMT enzyme levels (phenotype testing), what is the appropriate azathioprine dose in mg/kg/day for a patient with a (1) normal enzyme level, (2) intermediate enzyme level, and (3) low enzyme level? (Pg. 172) Q16.7 What is the clinical advantage of enteric­coated mycophe­ nolate (mycophenolate sodium)? (Pg. 182) Q16.13 What is the typical (1) starting dose for mycophenolate (mofetil and sodium formulations), and (2) therapeutically effective dose range for mycophenolate (mofetil and sodium formulations) (Pg. 185) Q17.3 What are the ‘off­label’ uses of CsA with the greatest lit­ erature support? (Pgs. 191,192)

779

Q17.10 What is the ‘approved’ maximum duration of continu­ ous therapy of CsA for psoriasis patients as published by (1) the United States consensus conference, and (2) the ‘worldwide’ consensus conference? (Pg. 195) Q18.3 What drugs inhibit phosphodiesterase 4 and for what dis­ eases are these drugs being used for? (Pgs. 200, 201, 202) Q18.4 What can be expected of apremilast in terms of efficacy for psoriasis and psoriatic arthritis, based on clinical trial re­ sults? (Pg. 201x2) Q18.7 What drugs inhibit the JAK/STAT pathway and for what diseases are these drugs used? (Pg. 203x6) Q19.1 Concerning cytotoxic drug use in dermatology, what are (1) five to six of the disease categories for which these drugs are used, and (2) the three most important adverse effect catego­ ries? (Pg. 209) Q20.1 What is the role of hydroxylamine metabolites in dapsone toxicities and how does cimetidine alter these effects? (Pg. 224) Q20.3 Concerning the myeloperoxidase system, (1) what are sev­ eral additional cells that use this enzyme, and (2) which dap­ sone­responsive dermatoses involve these cell types? (Pg. 226) Q20.5 Concerning bullous dermatoses responsive to dapsone, (1) what are several that are immunoglobulin A (IgA) medi­ ated, and (2) what are several other dapsone responsive immu­ nobullous dermatoses? (Pg. 227) Q20.6 What are several ‘neutrophilic dermatoses’ which typically respond to dapsone? (Pg. 227) Q21.2 In general, concerning responses of lupus erythematosus to antimalarials, (1) which cutaneous subsets respond well, (2) which cutaneous subsets respond less well, and (3) which systemic features/organ systems respond well? (Pg. 237) Q21.9 What is the recommended ‘maintenance’ dosage range, with an acceptably low incidence of retinopathy, for antimalar­ ial therapy with hydroxychloroquine or chloroquine therapy? (Pg. 242) Q21.11 In which important ways does the dosage scheme differ when antimalarial agents are used in porphyria cutanea tarda? (Pg. 243) Q22.5 How do (1) daily isotretinoin doses and (2) cumulative isotretinoin doses affect the likelihood of significant clinical re­ currence of acne vulgaris? (Pg. 250) Q22.6 How significant is the evidence for a chemopreventative effect of acitretin in (1) solid organ transplantation patients, and (2) other patients with frequent nonmelanoma skin can­ cer? (Pg. 251) Q23.10 What is the specific action spectrum of excimer laser? (Pg. 268) Q23.12 What are the three main indications for UVA­1 photo­ therapy? (Pgs. 269x2, 270) Q24.6 What are four prognostic factors for a favorable outcome with ECP in patients with erythrodermic CTCL? (Pg. 274) Q24.9 Aside from ECP for CTCL, what is the most promising additional dermatologic indication for ECP therapy? (Pg. 276) Q25.4 Which cells tend to have the greatest accumulation of ALA and MAL with topical application, and how do these sites of greatest absorption relate to conditions treated with PDT? (Pg. 281) Q25.7 What is the one US Food and Drug Administration (FDA)­approved indication for photodynamic therapy with ALA and MAL? (Pg. 283) Q25.8 What are the overall pros and cons for treating acne with photodynamic therapy using (1) ALA, (2) MAL, (3) the Blu­U light in the absence of either product? (Pg. 284)

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APPENDIX 1

Core Questions for Understanding Systemic Dermatologic Drugs

Q25.12 What are the pros and cons (limitations) of chemical and physical sunscreens subsequent to a photodynamic therapy treatment session? (Pg. 286) Q26.4 How do the maximum PASI­75 rates compare between the four TNF­α inhibitors? (Pgs. 291x2, 293, 295, 297) Q27.1 Which IL 12/23 inhibitor is currently approved for the treatment of psoriasis and which biologics are in development? (Pg. 303) Q27.4 What conclusions were drawn from the phase III ustekinumab trials with regard to efficacy? (Pg. 308) Q27.5 What conclusions can be drawn from the PSUMMIT 1 and 2 studies on the effect of ustekinumab on psoriatic arthri­ tis? (Pg. 308) Q27.7 How does interleukin [IL]­12/23 inhibitor compare to IL­17 inhibitors in the treatment of psoriasis in terms of Pso­ riasis Area Severity Index (PASI) score? (Pg. 308) Q28.7 What step is required prior to prescribing brodalumab and why is this extra step needed? (Pg. 318) Q29.4 How does the efficacy of IL­23 inhibition alone compare with IL­12/23 inhibition? (Pg. 321) Q29.5 What conclusions were drawn from the phase III gusel­ kumab trials with regard to efficacy? (Pg. 322) Q29.7 What conclusions were drawn from the phase III tildraki­ zumab trials with regard to efficacy? (Pg. 325) Q29.8 What conclusions were drawn from the phase III risanki­ zumab trials with regard to efficacy? (Pg. 326) Q29.9 In what other diseases may IL­23 inhibitors may have utility? (Table 29.4, Pg. 328) Q30.1 Rituximab is US Food and Drug Administration (FDA) approved for what dermatologic conditions? What are several categories of dermatoses for which off­label use of rituximab has at least some literature support? (Pg. 331x2) Q30.12 What are FDA­approved dosing schemes for (1) lym­ phoma patients, (2) rheumatoid arthritis? (3) granulomatosis with polyangiitis and microscopic polyangiitis and (4) pemphi­ gus vulgaris? (Pg. 336) Q31.1 For which category of patients with atopic dermatitis is dupilumab US Food and Drug Administration (FDA)­ap­ proved? (Pg. 339) Q31.5 What are two off­label dermatologic conditions in which dupilumab has been of benefit? (Pg. 341) Q32.9 Which is the most sedating of the ‘low­sedation’ second­ generation antihistamines, and how can this be an advantage or disadvantage, depending on clinical circumstances? (Pg. 354) Q33.2 Which drugs discussed in this chapter have demonstrated efficacy in patients with Raynaud phenomenon? (Pgs. 359, 364x3, 365, Box 33.1) Q34.2 For which skin disorders are antiandrogens and andro­ gen inhibitors clinically useful from a mechanistic standpoint? (Pgs. 367, 368) Q35.3 What is the basis of the tremendous dosing variation between patients receiving doxepin for depression or for pruritus (and how does this relate to doxepin­induced sedation)? (Pg. 386) Q36.2 What is the likelihood of success and unique risks when using IVIg for patients with severe, recalcitrant dermatomyo­ sitis? (Pg. 399) Q36.3 What is the likelihood of success and unique risks when using IVIg for patients with severe, recalcitrant pemphigus? (Pg. 400) Q36.5 What is the likelihood of success and unique risks when using IVIg for patients with Stevens­Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)? (Pg. 401)

Q36.9 What are the most common regimens for IVIg therapy regarding: (1) dosage per kilogram, (2) duration of therapy per cycle, and (3) interval between cycles? (Pg. 404) Q36.11 Overall, which conditions managed at least in part by derma­ tologists have the greatest evidence for efficacy of IVIg? (Pg. 404) Q37.9 What are the indications for dexamethasone in preventing or treating dermatologic adverse events associated with anti­ cancer drugs? (Pgs. 415x3, 416) Q38.1 What are the US Food and Drug Administration (FDA)­ approved indications for vismodegib and sonidegib? (Pg. 422x2) Q39.4 What are typical doses for (1) calcium, (2) vitamin D, and (3) various bisphosphonates in the prevention and man­ agement of corticosteroid­induced osteoporosis? (Pg. 434) Q39.10 Concerning vitamin D therapy (1) what is the mechanis­ tic role of vitamin D in corticosteroid osteoporosis prevention, and (2) what malignancies are possibly reduced by significant vitamin D intake? (Pg. 444) Q65.9 What are some of the drugs that present essentially no risk when taken in pregnancy? (Box 65.1, Pg. 714) Q65.10 What are the eight principles for safely using dermato­ logic drugs in pregnancy and lactation listed in the Summary section? (Pg. 724) Q67.6 Aside from drug discontinuation, what are several of the appropriate drug choices in treating DRESS? (Pg. 747) Q67.10 What are several of the most well­documented treatment options for SJS and TEN? (Pg. 751)

Section 3—Severe Adverse Effects Q2.3 What are several of the typical characteristics of the most worrisome adverse effects to systemic drug therapy (Pg. 13) Q2.6 What are three to four examples of major drug risks ‘discov­ ered’ many years after the drug’s release? (Pg. 15) Q2.11 In the event a potentially serious complication of drug therapy does occur, what are some of the most important man­ agement options available to clinicians? (Pg. 19) Q7.2 What are some recent examples of drugs removed from the market by the US Food and Drug Administration as a result of the pharmacovigilance process (as well as the reason for the drug being removed)? (Pg. 55) Q7.6 Why are ‘new’ adverse effects of medications so frequently discovered after a drug has already been approved for market­ ing as safe and effective? (Pg. 57) Q7.7 How is a ‘signal’ defined, regarding an important potential adverse effect caused by a drug; likewise, how are these signals generated in the pharmacovigilance process? (Pg. 58) Q8.3 How are the strongest possible warnings and strategies con­ cerning drug risks communicated through (1) boxed warnings, and (2) risk evaluation and mitigation strategies (REMS)? (Pg. 63) Q8.4 Concerning ‘Elements to Assure Safe Use’ strategies, what is (1) the purpose of these strategies with respect to REMS, and (2) a specific example pertinent to the daily practice of dermatology? (Pg. 63) Q9.4 What two drugs discussed in this chapter can induce a se­ rum sickness­like reaction? (Pgs. 78, 84, 91, 95, 96) Q9.14 What are several relatively unique hypersensitivity and au­ toimmune reactions caused by minocycline? (Pgs. 88x2, 89) Q9.18 What are antibacterial agents with a risk of antibiotic­ associated colitis due to Clostridium difficile? (Pgs. 77, 88) Q10.12 What are the rare severe dermatologic adverse events reported for terbinafine, itraconazole, and fluconazole? (Pgs. 110, 111x2)

APPENDIX 1 Core Questions for Understanding Systemic Dermatologic Drugs

Q13.7 What are several of the most important adverse effects of systemic CS that can lead to significant, irreversible morbidity (as well as measures to prevent/monitor for these complica­ tions)? How do patient comorbidities impact the risk of these conditions? (Table 13.7, Pgs. 142, 144) Q13.8 What are at least four to five of the potentially life­threat­ ening complications of systemic CS, and what are some of the important measures to prevent and/or monitor for these com­ plications? (Table 13.8, Pg. 143) Q14.5 What are the most important risk factors for methotrex­ ate­induced liver disease? (Pg. 162) Q14.7 Why is even a mild–moderate reduction in renal function important regarding the safe use of methotrexate? (Pg. 164) Q14.8 Is there any definitive evidence that methotrexate increas­ es the risk of lymphomas in psoriasis patients? (Pg. 165) Q15.6 How does the incidence of lymphoproliferative malignan­ cies and cutaneous squamous cell carcinomas differ in patients receiving azathioprine for dermatologic diseases, rheumatoid arthritis, and solid organ transplantation? (Pg. 173) Q15.8 What are the important clinical features of the hypersensi­ tivity syndrome occasionally induced by azathioprine? (Pg. 175) Q16.8 What is the mycophenolate increased risk of (1) lympho­ ma in solid organ transplantation patients, and (2) non­mel­ anoma skin cancers in this population of patients? (Pg. 182) Q16.10 What is the likelihood that mycophenolate truly induces progressive multifocal leukoencephalopathy (PML)? (Pg. 184) Q16.11 Why was a boxed warning added regarding pregnancy? (Pg. 184) Q17.5 What is the risk (if any) of the following from appropriate use of CsA in dermatologic patients: (1) non­melanoma skin cancer, and (2) lymphoproliferative disorders? (Pg. 193) Q18.8 What are the Boxed warnings in the prescribing informa­ tion for tofacitinib? (Pgs. 204, 205x2) Q19.11 Concerning cyclophosphamide and bladder cancer, what is (1) the metabolite responsible, (2) the condition commonly preceding the cancer, (3) the nonmedical preventative measure, and (4) the most effective medical management preventative step? (Pgs. 215x2, 218x2) Q19.12 Concerning malignancy risk from cyclophosphamide or chlorambucil (other than bladder cancer from cyclophospha­ mide), (1) what malignancies are increased (include one that is ‘unique’), and (2) what populations tend to be at especially increased risk? (Pgs. 217, 220) Q20.11 Concerning dapsone agranulocytosis, what are (1) the incidence, (2) typical timing, (3) clinical presentation, and (4) resolution after dapsone discontinuation? (Pg. 229) Q20.12 Concerning dapsone neuropathy, what are (1) the clini­ cal presentation, (2) the role of dapsone dose, and (3) resolu­ tion after dapsone discontinuation? (Pg. 230) Q20.13 What is the typical timing and presentation of dapsone hypersensitivity syndrome (subset of drug reaction with eosin­ ophilia and systemic symptoms [DRESS])? (Pg. 230) Q21.5 Concerning retinal toxicity with chloroquine and hy­ droxychloroquine, (1) what is the difference between ‘premac­ ulopathy’ and ‘true retinopathy’, and (2) which of these find­ ings is irreversible? (Pg. 239) Q21.7 What are some of the most important risk factors for reti­ nal toxicity from antimalarial therapy? (Pg. 240x2) Q22.7 What are the primary components of the retinoic acid embryopathy, and what timing in relation to conception pres­ ents the greatest risk of these serious congenital malformations? (Pg. 252)

781

Q22.9 How do epidemiologic studies of depression risk from isotretinoin compare with case series suggesting a possible id­ iosyncratic risk of depression in occasional individuals on this drug? (Pg. 256) Q22.10 What does the preponderance of evidence suggest re­ garding a possible causal role of isotretinoin inducing inflam­ matory bowel disease? (Pg. 256) Q23.4 What is the true risk of melanoma from long­term PUVA photochemotherapy? (Pg. 266) Q24.2 What are the potential cardiovascular and thromboem­ bolic risks of ECP? (Pg. 272) Q26.8 Is the risk of lymphoma in patients receiving TNF­α in­ hibitors elevated compared to the baseline risk in autoimmune diseases such as psoriasis and rheumatoid arthritis? (Pg. 298) Q27.9 Is there an association between IL­12/23 inhibitors and major adverse cardiovascular events (MACE)? (Pg. 309) Q28.8 How common are infections while on IL­17 inhibitors and what type of infections usually occur? (Pg. 318) Q30.6 How does rituximab use affect vaccination with live and non­live vaccines? (Pg. 332, 336) Q30.10 Rituximab carries Boxed Warnings for reactivation of what two viral infections? (Pg. 336x2) Q31.10 Omalizumab carries a boxed warning. What is it, and how is it related to drug dosing? (Pg. 344) Q33.5 Which severe adverse event has been reported in pediatric patients receiving propranolol therapy for complicated infan­ tile hemangiomas? What advice can be given to minimize this risk? (Pg. 362) Q34.6 What are the primary recommendations for women re­ ceiving spironolactone concerning the possibility of estrogen­ dependent malignancies (including data for/against this risk)? (Pg. 372) Q37.12 How long do cutaneous squamous cell carcinoma (cuS­ CC) occur after initiation of drug therapy with vemurafenib? (Pg. 418) Q38.4 What does the evidence suggest regarding Hh inhibitor risk to the embryo/fetus in pregnant females? (Pg. 424x2) Q40.13 Aside from teratogenicity, what is the most important adverse effect from thalidomide? (Pgs. 460, 461) Q62.2 What are several of the drugs removed from the United States market because of severe liver toxicity? (Pg. 678) Q62.6 What is typical timing of DILI concerning (1) onset of the reaction after the drug therapy was initiated, and (2) time prior to resolution after drug is stopped? (Pg. 681) Q62.8 What are several of the reasons that clinical trials before a drug’s approval for marketing may not detect many of the relatively uncommon idiosyncratic adverse liver events caused by drugs? (Pg. 683) Q62.9 What are four categories of DILI of greatest relevance to dermatologists (and what are several drugs that induce these patterns of liver injury)? (Pg. 683, Table 62.7) Q63.5 Using multiple large population studies, what are some of the most important drugs (dermatologic and nondermato­ logic) with an increased risk of agranulocytosis? (Pg. 691) Q63.7 Between drug­induced lymphoproliferative malignancies and leukemias, which are more likely to be reversible on cessa­ tion of drug therapy? (Pg. 692) Q64.2 What are the pros and cons of using surveillance epidemi­ ology and end results (SEER) database in the United States as a ‘control group’ (or comparable databases for other countries) compared with disease­specific databases in determining the risk of drug­induced malignancy? (Pg. 702)

782

APPENDIX 1

Core Questions for Understanding Systemic Dermatologic Drugs

Q64.4 Which malignancies that are definitely increased (non­ Hodgkin lymphoma, Merkel cell carcinoma, cutaneous squa­ mous cell carcinoma [SCC], and Kaposi sarcoma) and possibly increased (melanoma) in solid organ transplantation have a proven/possible viral cofactor respectively? (Pgs. 703, 704) Q64.9 What is similar and what is different concerning the risk of SCC, basal cell carcinoma, and melanoma from Psoralen and ultraviolet A therapy compared with organ transplantation immunosuppression regimens? (Pg. 707) Q64.10 What are several specific measures (for patients and phy­ sicians) for prevention and early diagnosis of malignancies defi­ nitely or possibly increased by immunosuppression? (Pg. 707) Q65.6 Which drugs prescribed by dermatologists are considered contraindicated in pregnancy? (Table 65.3, Pg. 712) Q67.1 Which drugs or drug groups most commonly induce the drug reaction with eosinophilia and systemic symptoms (DRESS)? (Pg. 743) Q67.2 Which anticonvulsants have the potential to cause DRESS; to which category do all but one of these anticonvul­ sants belong? (Pg. 745, 746) Q67.9 What three drug categories most commonly induce Ste­ vens­Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)? (Pg. 750)

Section 4. Less Serious Adverse Effects Q12.5 What are the four most common ivermectin adverse ef­ fects when used to treat helminth infestations? (Pg. 127) Q14.3 What are the pros and cons of routine folic acid supple­ mentation with methotrexate therapy? (Pgs. 159, 163x2, 165) Q17.7 What are some of the possible interventions for the rela­ tively common significant elevations of triglycerides or choles­ terol with CsA therapy? (Pg. 193) Q18.5 What is the most common adverse effect experienced by patients on apremilast? (Pgs. 201, 202) Q19.7 What are two to three of the unique cutaneous adverse effects of hydroxyurea? (Pg. 214) Q22.11 How does bexarotene­induced hypothyroidism differ from most cases of hypothyroidism seen in clinical practice? (Pg. 257) Q23.3 What is the risk of squamous cell carcinoma (SCC) from long­term psoralen plus UVA (PUVA) therapy and are these more biologically aggress than actinically­induced SCC? (Pg. 266) Q23.8 Does NB­UVB have a defined risk for nonmelanoma skin cancer? (Pg. 268) Q26.3 Of the four TNF­α inhibitors discussed in this chapter, which are the most immunogenic? (Pgs. 290, 292, 293x2, 294, 295, 296) Q30.9 What is the most common adverse effect from rituximab and what preventative measures reduce this risk? (Pgs. 335, 337) Q31.6 What is the most common adverse event with dupilumab, and how can it be prevented and/or minimized? (Pg. 342) Q33.4 What are several of the common mucocutaneous adverse effects from calcium channel blockers? (Pg. 361) Q34.10 What are the effects of finasteride on sexual function, if any? (Pg. 377) Q35.4 What are some of the most important measures to mini­ mize the risk from sedation in patients receiving doxepin ther­ apy? (Pg. 386) Q35.6 What is meant by the term ‘discontinuation symptoms’ and what are some of the therapeutic options in dealing with these symptoms? (Pgs. 387, 388, 390)

Q35.7 What are the most common adverse effects of the selec­ tive serotonin reuptake inhibitors (SSRI), and what are some measures for reducing these adverse effects? (Pg. 388) Q35.8 Which drugs in this chapter have the risk of inducing sexual dysfunction? (Pgs. 388, 390x2, 391) Q37.2 Which drug class is most commonly associated with an acneiform papulopustular eruption? (Pg. 406) Q37.6 How does the hand–foot syndrome associated with an­ thracyclines differ from the hand–foot skin reaction induced by sorafenib? (Pg. 413) Q38.3 What are potential adverse effects of vismodegib and sonidegib? (Pgs. 424x3, 426, 427) Q39.3 What are the reasons that oral bisphosphonates must be taken in a fasting state and in an upright position? (Pg. 433) Q40.6 What are several measures that reduce the common col­ chicine gastrointestinal effects? (Pg. 451) Q40.10 What is the most important systemic adverse effect of potassium iodide? (Pg. 457x2) Q40.11 What are several of the most common mucocutaneous adverse effects of potassium iodide? (Pg. 457)

Section 5 - Drug Safety Monitoring Q2.2 How are the ‘standards of care’ for drug therapy monitoring determined? (Pg. 13) Q2.8 What are the most important common clinical scenarios which require more frequent (compared to normal monitoring frequencies) laboratory monitoring? (Pg. 18) Q2.9 What are some important examples of ‘thresholds of con­ cern’ and ‘critical values’ for laboratory tests commonly used in drug monitoring (Table 2.1)? (Pg. 18) Q14.6 What are some of the noninvasive tests available to evalu­ ate liver fibrosis with methotrexate therapy? (Pg. 163) Q14.11 What are the practical guidelines concerning which psoriasis patients should have a (1) true baseline liver biopsy, (2) a delayed baseline liver biopsy, and (3) an initial biopsy at 1.5 g cumulative dose? (Pg. 166x2) Q15.1 What are the pros and cons of ordering baseline testing for thiopurine methyltransferase (TPMT) enzyme activity (phe­ notype) prior to initiating azathioprine therapy? (Pg. 170x2) Q15.7 What is a reasonable lower limit for a white blood cell count during azathioprine therapy and what are some measures clinicians can use when this lower limit is passed? (Pg. 174) Q15.10 Why is hepatic monitoring of importance in following patients receiving azathioprine therapy? (Pg. 176) Q17.4 Concerning possible renal toxicity with CsA therapy for psoriasis, (1) what is the rationale behind the monitoring guidelines, and (2) what are the appropriate dosage adjust­ ments of CsA with specific elevations of serum creatinine lev­ els? (Pgs. 192, 193) Q18.9 What laboratory monitoring is recommended for patients taking tofacitinib? (Pg. 206x3) Q20.8 What are several ethnic groups which are more likely to be glucose­6­phosphate dehydrogenase (G6PD) deficient and how does this impact ordering baseline determination of G6PD in all groups? (Pg. 229) Q21.4 How do the 4­aminoquinolines (such as hydroxychlo­ roquine) and 8­aminoquinolines (such as primaquine) differ in the need for a baseline glucose­6­phosphate dehydrogenase (G6PD) determination? (Pgs. 239, 241) Q22.8 How do the various systemic retinoids affect triglyceride and cholesterol levels to varying degrees? (Pg. 255)

APPENDIX 1 Core Questions for Understanding Systemic Dermatologic Drugs

Q24.7 On flow cytometry of peripheral blood, which T­cell markers are most useful in monitoring the patient’s response to ECP? (Pg. 275) Q26.5 What is the risk of reactivation of hepatitis B or hepatitis C virus in patients treated with TNF­α inhibitors? (Pgs. 292, 299) Q26.9 Why is it important to order a baseline PPD or interferon­ γ release assay (such as Quantiferon Gold or Tspot TB) before initiation of TNF­α inhibitor therapy? (Pg. 299) Q27.10 Is the development of human antidrug antibody forma­ tion a valid concern for treatment efficacy for ustekinumab? What role do drug levels play in assessing the impact? (Pg. 310) Q28.9 What condition(s) should patients be screened for prior to starting an IL­17 inhibitor? (Pg. 319) Q28.10 Which screening tests should be performed prior to starting a patient on anti IL­17 therapy? (Pg. 319) Q30.11 How common are human antichimeric antibodies to rituximab in lymphoma and autoimmune diseases? What are possible consequences of these antibodies? (Pg. 336) Q30.13 What laboratory tests are suggested prior and subse­ quent to rituximab therapy? (Pg. 337) Q34.11 What is the effect of finasteride on prostate­specific an­ tigen (PSA) levels, and how should values for this test be ‘ad­ justed’ for men receiving finasteride? (Pg. 378) Q36.6 What is the rationale for ordering immunoglobulin levels for patients who are about to receive IVIg therapy? (Pg. 403x2) Q62.10 For which systemic drugs prescribed by dermatologists is the need to monitor for liver toxicity not widely ‘known’? (Pg. 684x2) Q62.12 What do various liver ‘function’ tests truly evaluate in DILI? (Pg. 686, Table 62.10) Q63.1 What are two enzymes for which baseline testing serves to predict patients at risk for hematologic toxicity from drugs commonly used in dermatology? (Pg. 690, 694, 695) Q63.9 What are some of the numerical guidelines for drug dosage reduction or drug cessation with reduced counts for: (1) neutrophils, (2) total white blood cell counts, and (3) plate­ lets? (Pg. 698)

Section 6—Drug Interactions (see also Appendix 2) Q9.3 What are some of the drugs with the potential for a cross­ reaction in patients allergic to penicillins, and what is the true risk (frequency and magnitude) of such cross­reactions? (Pgs. 73, 77) Q9.9 Concerning macrolides and azalides, what are some impor­ tant differences in (1) infections most effectively treated, and (2) cytochrome P­450–drug interactions? (Pgs. 79, 82, 89) Q9.17 What is the scientific basis for various antibacterial groups possibly reducing the effectiveness of hormonal contraceptives? (Pg. 90x2) Q10.13 Considering all four main systemic antifungals discussed, which is (1) the strongest cytochrome P­450 (CYP)3A4 in­ hibitor, (2) a CYP2D6 inhibitor, (3) a CYP3A4 inducer, and (4) a CYP2C9 inhibitor (and the most important drug interac­ tions with each)? (Pg. 111x2, Tables 10.6 and 10.7) Q10.14 Considering all four main systemic antifungal agents in this chapter, which has drug interactions with a risk of (1) tor­ sades de pointes, and (2) inducing an increased international normalized ratio? (Pg. 111x2) Q14.9 Which drug interactions have the most serious potential with methotrexate therapy? (Pg. 165, Fig. 14.3, Table 14.1)

783

Q15.3 Concerning azathioprine drug interactions, (1) what is the most important drug interaction and its mechanism, and (2) what are several other important interactions? (Pg. 171) Q17.8 What are several of the most important drug interactions with CsA therapy? (Pg. 193, Table 17.4) Q20.15 What are the key issues to consider regarding sulfon­ amide and dapsone cross­reactivity? (Pg. 231) Q34.7 What are the most important drug interactions for spi­ ronolactone/drospirenone? (Pgs. 373, 375) Q34.13 Which drugs truly alter hormonal levels of hormonal contraceptives through the cytochrome P­450 system, and can therefore definitively lead to contraceptive failure? (Pg. 380) Q35.12 Concerning cardiac complications because of QT­interval prolongation, what are measures to diagnose and manage this risk with (1) pimozide, and (2) risperidone? (Pgs. 393x2) (also Pg. 388) Q39.7 Why was cerivastatin taken off the market by the US Food and Drug Administration (FDA); what is the risk of this same complication in the remaining ‘statins’? (Pgs. 436, 438) Q39.8 Concerning drug interactions with the statins, which drugs in this class do not interact with drugs (such as cyclospo­ rine) metabolized by the CYP3A4 pathway? (Pg. 436) Q40.1 What are several important drug interactions with anti­ cholinergic drugs discussed in this chapter? (Pg. 446) Q66.1 What are several drugs with a narrow therapeutic index, which increases the likelihood of relatively serious drug interac­ tions? (Pg. 726) Q66.7 What is one general mechanism by which adding a CYP inducer to a substrate drug can lead to significant drug toxic­ ity? (Pg. 736) Q66.8 What is the clinical importance of QTc prolongation type drug interactions that (1) occur at therapeutic drug concen­ trations, and (2) those which occur only with elevated drug concentrations? (Pg. 736, Box 66.10) Q67.4 In cases of DRESS caused by sulfonamide antimicrobials, what is the risk of a cross­reaction to related sulfonamides that are not aromatic amines? (Pg. 746) Q67.5 In cases of DRESS caused by minocycline, what is the risk of a cross­reaction to doxycycline or tetracycline? (Pg. 746)

Section 7—Miscellaneous Issues Q7.4 What are some of the most important limitations of randomized controlled trials in generating drug safety data? (Pg. 55) Q7.9 What are the advantages and disadvantages of meta­analyses in analyzing drug safety? (Pg. 58) Q8.2 What is the individual purpose of each of following sec­ tions of the product label: (1) clinical studies, (2) adverse reac­ tions, (3) warnings and precautions, and (4) contraindications? (Pg. 63x2) Q8.6 What are five to six of the online sources for ‘electronic’ in­ formation from the FDA concerning drug safety information? (Pg. 64) Q63.4 What are some issues important to proper analysis of large population studies on hematologic toxicities, including factors leading to overestimates and underestimates of risk? (Pg. 690) Q65.1 How did the 2015 Pregnancy and Lactation Labeling Rule change the US Food and Drug Administration (FDA) format of drug labeling? (Pg. 711)

Appendix

II

The Most Potentially Serious Drug Interactions General Principles for Creating This Appendix (1) ‘Potentially serious’ designation based on potential (however rare) for fatality or severe irreversible morbidity. (2) Left column for drugs or drug groups potentially prescribed by dermatologists (all are orally administered). (3) Middle column for drugs or drug groups the patient is already taking (virtually all are orally administered).

(4) Right column used for explanation of interaction mechanism; the outcome(s) of the interaction that lead(s) to ‘potentially serious’ interaction status is/are listed in bold. (5) Majority of above interactions on pharmacokinetic (PK) basis, most having CYP mechanisms; the minority are pharmacodynamic basis designated (PD) in middle column. (6) In many drug categories, the interaction risks vary within the category; these are listed in descending order of risk with ‘>>’ = larger difference, and ‘>’ = smaller difference.

Specific Drugs/Groups

Interacting Drug Examples

Comments

Azathioprine

Allopurinol, febuxostat

Effect is ↑ 6-MP → ↑ 6-TG metabolites attributed to ↓ xanthine oxidase leading to myelosuppression; greater effect with ↓ TPMT baseline; if no suitable alternatives, can give azathioprine 1⁄3 to ¼ typical dose 6-thiopurines (such as azathioprine) together with TNF inhibitors unique risk aggressive hepatosplenic T-cell lymphoma and potentially other T-cell lymphomas (particularly young male IBD patients)

Infliximab, etanercept, adalimumab, certolizumab (PD) Cyclosporine

Erythromycin >> clarithromycin > azithromycin Ketoconazole >> itraconazole > fluconazole (only >200 mg daily) Diltiazem, verapamil Rifampin, rifabutin, rifapentine

Gentamicin, tobramycin, TMP/SMX, vancomycin (PD)

CYP3A4 inhibitors, which ↑ CsA drug levels and resultant toxicity—renal toxicity, HBP, ↑ lipids, etc same same (all other CCB are just CYP3A4 substrates, not inhibitors) CYP3A4 induction with resultant ↓ CsA drug levels and loss efficacy; this effect takes 1-2 weeks; most important with solid organ transplantation rejection, more severe autoimmune conditions Potentially renal toxic drugs which in combination ↑ risk of CsA renal toxicity (possibly also HBP)

Doxycycline, minocycline, tetracycline

Isotretinoin (PD)

Pseudotumor cerebri = idiopathic intracranial hypertension; most reports in 1980s

Epinephrine

Propranolol, nadolol, timolol (PD)

Potential for malignant hypertension attributed to unopposed epinephrine effects

Fluconazole (any dose)

Warfarin (S-enantiomer)

CYP2C9 inhibitor; S-enantiomer of warfarin major substrate pathway (most important) risk severe bleeding

Fluoroquinolones

Warfarin (R-enantiomer)

R-enantiomer most important substrate of CYP1A2; risk severe bleeding, check INR frequently

Hydroxychloroquine

Chloroquine (4-aminoquinolines) (PD)

Retinal toxicity risk ↑ with these drugs in combination (not a risk with quinacrine in combination with hydroxychloroquine)

Immunosuppressants

Wide variety—relatively uncommon to have these SAE in dermatology (PD)

Biologics, JAK inhibitors, traditional (azathioprine, cyclosporine, mycophenolates, etc), chemotherapy, higher dose CS with risk of severe infections and/or myelosuppression (when used in combination)

Itraconazole (all doses), fluconazole (>200 mg)

Cyclosporine (and oral tacrolimus)

CYP3A4 inhibitors ↑ drug levels and risk of severe toxicity renal toxicity, HBP, ↑ lipids, etc same (risk myopathy, rhabdomyolysis)

784

Simvastatin, atorvastatin, lovastatin

APPENDIX II The Most Potentially Serious Drug Interactions

Specific Drugs/Groups

Interacting Drug Examples

Comments

Methotexate, TMP/SMX, or dapsone

DHPS—sulfamethoxazole, dapsone

Sulfonamides, dapsone inhibit first enzyme in two-step folate reduction pathway → myelosuppression Methotrexate, trimethoprim inhibit second enzyme in folate reduction pathway → myelosuppression

DHFR—methotrexate, trimethoprim Methotrexate

Acitretin (PD)

785

Furosemide, ethacrynic acid, NSAID

Concomitant long-term use of both drugs with possible outcome of chronic liver disease due to fatty liver and possible fibrosis May ↑ MTX serum levels ↓ renal excretion and potential ↑ renal toxicity

Prednisone, other CS

Insulin, OHGA, other DM drugs (PD)

↑ insulin resistance with resultant potential for severe hyperglycemia

Rifampin, rifabutin, rifapentine

Cyclosporine, (oral) tacrolimus

Major loss of efficacy interaction takes 1–2 weeks to begin (potentially life-threatening when used in solid organ transplantation rejection, more severe autoimmune conditions Risk thromboembolic disorders CYP1A2/2C9 major pathway inducers R-/Senantiomers warfarin respectively; CYP3A4 minor pathway R-enantiomer)

Warfarin Spironolactone

ACE inhibitors, angiotensin II receptor blockers, drospirenone/Yaz (PD)

Concomitant use with spironolactone may augment the hyperkalemia potential of drug/drugs; conceptually higher/highest risk for these categories in older patients with CV and/or renal disease

SSRI antidepressants

Doxepin, amitriptyline

Paroxetine, fluoxetine strong CYP2D6 inhibitors ↑ TCAD levels; also (sertraline, citalopram, escitalopram much weaker CYP2D6 inhibitors); risk excessive sedation, dysrhythmias, orthostasis

Statins (simvastatin, atorvastatin, lovastatin)

Erythromycin >> clarithromycin > azithromycin Ketoconazole >> itraconazole > fluconazole (only >200 mg daily) Diltiazem, verapamil

CYP3A4 inhibitors which ↑ statin drug levels and resultant toxicity— myopathy, rhabdomyolysis same

Pimozide

CYP2D6 substrate pimozide significant risk QTc prolongation risk serious arrhythmias (see Chapter 66 Drug Interactions for more details on QTc prolongation interactions) Doxepin/amitriptyline CYP2D6 substrates ↑ TCAD levels; risk excessive sedation, dysrhythmias, orthostasis

Terbinafine

Doxepin, amitriptyline, venlafaxine

same (all CCB are CYP3A4 substrates; these two drugs are also inhibitors)

Thalidomide

Phenytoin, carbamazepine, phenobarbital Rifampin, rifabutin, rifapentine

CYP3A4 inducers; impair hormonal contraception in women of childbearing potential; risk severe teratogenicity same

Tricyclic antidepressants (focus doxepin, amitriptyline)

Paroxetine, fluoxetine (SSRI)

Primary CYP2D6 inhibitors of drug group; doxepin/amitriptyline CYP2D6 substrates ↑ TCAD levels; risk excessive sedation, dysrhythmias, orthostasis same same

Venlafaxine > bupropion (NSRI) Terbinafine

6-MP, 6-mercaptopurine; 6-TG, 6-thioguanine; ACE, angiotensin converting enzyme; CCB, calcium channel blockers; CS, corticosteroids; CsA, cyclosporine; CV, cardiovascular; DHFR, dihydrofolate reductase; DHPS, dihydropteroate synthetase; DM, diabetes mellitus; HBP, hypertension/high blood pressure; IBD, inflammatory bowel disease; INR, international normalized ratio; JAK, janus kinase; MP, mercaptopurine; MTX, methotrexate; NSAID, nonsteroidal anti-inflammatory drug; NSRI, nonselective reuptake inhibitors; OHGA, oral hypoglycemic agents; PD, pharmacodynamic; QTc, QT interval corrected; SAE, serious adverse effects; SSRI, selective serotonin reuptake inhibitors; TCAD, tricyclic antidepressants; TMP/SMX, trimethoprim/sulfamethoxazole; TNF, tumor necrosis factor; TPMT, thiopurine methyltransferase.

Index

A Abacavir, HLA markers, 31t Ab-dependent cellular cytotoxicity, rituximab, 331 ABI (ankle–brachial blood pressure ratio/ index), 598 Abrasive approaches, dandruff treatment, 582 Absorption, 22 aminolevulinic acid, 280–281 cyclosporine, 22t eutectic lidocaine and prilocaine, 641 ketoconazole, 22t methyl aminolevulinate, 280–281 mycophenolate mofetil, 22t percutaneous. see Percutaneous absorption P-glycoprotein, 22 pharmacokinetics, 2, 2t psoralens, 264 systemic retinoids, 248 Absorption agents, 763t Absorption enhancers, 762 ABT-874. see Briakinumab (ABT-874) ACCEPT, ustekinumab, 305, 308 Accidental effects, drug safety, 13 Accreditation Commission for Health Care (ACHC), 761 ACD. see Allergic contact dermatitis (ACD) ACE inhibitors, 90t Acetaminophen overdose, 680 pediatric dosing, 769t pregnancy/lactation risks, 717t Acetylsalicylic acid. see Aspirin N-Acetyltransferase phase II drug metabolism, 29 polymorphisms, 29, 29t N-Acetyltransferase-2 (NAT2), polymorphisms, 27t, 29 Acidic drugs, distribution effects, 3–4 Acitretin, 246 absorption/distribution, 248 adverse reactions hepatotoxicity, 686t teratogenicity, 252–254, 713t with broadband UVB (ReUVB), 250 with cyclosporine, 250 indications, 249–251

Acitretin (Continued) with methotrexate, 250 monitoring, 259b pharmacology, 247t pregnancy/lactation risks, 723t reesterification (reverse metabolism), 248 Acne fulminans, 255 Acneiform eruptions, chemical peels, 595 Acne vulgaris androgens, 367 development, 536–537 nonsteroidal anti-inflammatory drugs, 454 treatment azelaic acid, 473t, 477 benzoyl peroxide, 472–474, 473t chemical peels, 595 cimetidine, 375 clindamycin, 473t, 475 dapsone, 473t drosperinone, 375 erythromycin, 473t, 476 finasteride, 377 fluoroquinolones, 81 α-hydroxy acids, 588 metronidazole, 473t, 477 photodynamic therapy, 284 salicylic acid, 609 sodium sulfacetamide, 473t spironolactone, 371 sulfur, 612 systemic retinoids, 250–251 tetracyclines, 85 tretinoin, 529 see also specific types Actinic keratoses (AK), treatment, 285–286 photodynamic therapy, 283–284 retinoids, 537 Active pharmaceutical ingredients (API), 762 Acute hypersensitivity reactions, epinephrine, 644 Acute kidney injury (AKI), 497 Acute necrotizing ulcerative gingivostomatitis, 671 Acute vestibular side effects (AVSE), tetracyclines, 87

Acyclovir adverse effects, 119 drug interactions, 119 enzyme inhibition, 6t human herpes virus infections, 115–119 indications, 115–118, 118b chickenpox, 118 herpes simplex virus infections, 115–118 herpes zoster, 118 pediatric dosing, 769t pharmacology, 117t pregnancy/lactation risks, 721t risks, 118b Acyclovir, topical, 494–496, 495t adverse reactions, 494 indications, 494–496 mechanism of action, 494 pharmacology, 494 pregnancy, 494 structure, 494, 496f therapeutic guidelines, 494–496 Acyl CoA–retinol acyltransferase (ARAT), 532 Adalimumab, 289t, 295–297 adverse effects, 296 adverse reactions, malignancy induction, 701t, 705t, 706 biosimilars, 297 clinical trials, 295 contraindications, 296 dosage, 295 drug interactions, 296 indications, 291b, 295–296 psoriasis, 295 monitoring guidelines, 296 off-label uses, 296 pediatric patients, 775 pharmacology, 295 pregnancy/lactation risks, 723t therapeutic guidelines, 296 Adapalene pregnancy/lactation risks, 718t structure, 530f Adapalene, topical, 529t, 534 application guidelines, 537 indications, 536t mechanism of action, 529, 530t–531t

Note: Page numbers followed by “f ” indicate figures, “t” indicate tables, and “b” indicate boxes. 787

788

Index

Adapalene, topical (Continued) pharmacology, 531t precautions, 535t ADCC (antibody-dependent cellular cytotoxicity), rituximab, 331 Adherence, 34–39 costs, 34 improvement strategies, 36–39 importance, 37–38, 37b physician–patient relationship, 36, 36f, 36b special groups, 38–39, 38t treatment choice, 36–37, 37b influencing factors, 35–36, 35t magnitude, 35 measures, 34–35 Adipose tissue, distribution effects, 2–4 Adolescents, photodynamic therapy, 285 Adrenal crisis, 143, 149–150 Adrenaline. see Epinephrine ADRs. see Adverse drug reactions (ADRs) Adverse drug reactions (ADRs), 6t, 56 adherence effects, 37 costs, 21 definitions, 6t, 21 hematologic toxicity. see Hematologic toxicity HLA markers, 31t influencing factors, 22 liver toxicity. see Hepatotoxicity malignancies. see Malignancy induction neurological system. see Neurologic adverse reactions patient evaluation, 22 polymorphisms, 22, 31 randomized controlled trials (RCTs), 56 rare, 56 signal generation, 58 systemic features see also specific diseases/disorders type A (pharmacologic), 55 type B (idiosyncratic/allergic), 55 type C (new disease), 55, 59t see also specific drugs. Adverse Event Reporting System (AERS), 57–58 Adverse Events Reports, 63 Adverse Reactions section, labeling, 63 Advisory panels, Federal and Drug Administration, 51 AERS (Adverse Event Reporting System), 57–58 Aesthetics, tar adverse reactions, 614 Affinity, definition, 5t AGA, treatment cimetidine, 375 dutasteride, 378 Age, percutaneous absorption, 10t Agonists definition, 5t drug receptors, 4–6, 5t partial, 5t receptors, 5t

Agranulocytosis, 229–230 Agranulocytosis, drug-induced, 690 as adverse reactions, 690 dapsone, 695 management, 695, 698 Agranulocytosis treatment, spironolactone, 372–373 AHA. see α-hydroxy acids (AHA) α-Hydroxy acids, 585–587, 587t adverse reactions, 590 bioavailability, 589–590 combination products, 588 definition, 585 dermal effects, 586, 587t epidermal effects, 586 formulations, 589–590 historical aspects, 590 indications, 585, 587–589 acne vulgaris, 588 actinic keratoses, 589 chemical peels, 589 dermatoheliosis, 587–588 hyperpigmentation, 588 ichthyosis, 587 nail disorders, 589 pigmented lesions, 588 psoriasis, 588–589 rhytides, 587–588 xerosis, 587 mechanisms of action, 586–587 pharmacology, 585–587 prescription vs. over-the-counter, 587–588 structure, 585–586, 586f with tretinoin, 588 α-hydroxy acids (AHA) see also specific compounds AIDS-associated Kaposi’s sarcoma treatment retinoids, 538–539 AIN-457 (secukinumab), 308–309 AK. see Actinic keratoses (AK) Akathisia, pimozide adverse reactions, 393 ALA. see Aminolevulinic acid (ALA) Alanine aminotransferase. see AST/ALT Albaconazole, 100 Albendazole, 131t, 509 adverse effects, 129 dosing, 129t drug interactions, 129 formulations, 509t indications, 129 mechanism of action, 128 pharmacology, 128 pregnancy, 129 resistance, 129 therapeutic guidelines, 129 Albumin bioavailability, 4 liver function tests, 686, 687t Alefacept, malignancy induction, 701t, 706t Alemtuzumab, 407t, 416 adverse reactions, 409t indications, 408t

Alendronate, 431, 431f, 432t administration, 432 metabolism, 431 osteoporosis prevention, 432 pregnancy, 433 structure, 431f therapeutic guidelines, 434 Alitretinoin, 247 structure, 529 Alitretinoin, topical, 529t–531t, 536 indications, 536t AIDS-related Kaposi’s sarcoma, 538–539 Kaposi’s sarcoma, 536 pharmacology, 531t precautions, 535t structure, 529 Alkaline phosphatase, liver function tests, 686, 687t Alkanones, 454t Alkylating agents, 214–221, 407t, 414 chlorambucil, 218–220 cyclophosphamide, 214–218 indications, 408t malignancy induction, 701t, 705–706 melphalan, 220–221 see also specific drugs. Allergens, 617–622 topical contact. see Contact allergens; topical Allergic contact dermatitis (ACD), 468, 617–618 corticosteroid adverse reactions, 521, 521b shampoo adverse reactions, 581 sunscreen adverse reactions, 572 vitamin D3 adverse reactions, 563 Allergies contact. see Contact allergy injectable local anesthetics, 639 see also specific allergies Allopurinol, adverse reactions aplastic anemia (pancytopenia), 694 HLA markers, 31t All-trans retinoic acid (ATRA), 248, 529t indications, 536t mechanism of action, 530t–531t pharmacology, 531t precautions, 535t Allylamines, 482t, 486–487 anti-inflammatory properties, 490 drug interactions, 738 in vitro and in vivo activity of, 483t mechanism of action, 103 topical see also specific agents see also specific drugs. Aloe vera, 629 Alopecia definition, 411t–412t treatment, finasteride, 376–377 Alopecia areata, treatment, 628 anthralin, 628–629 corticosteroids, 518 PUVA, 265

Index

α-1-acid glycoprotein (AAG), 420 Alprazolam, anxiety treatment, 385 American Society for Apheresis (ASFA), 276 Aminobenzoic acid, sunscreens, 567t Aminoglycosides see also specific drugs. Aminolevulinic acid (ALA) absorption, 280–281 bioavailability, 280–281 contraindications, 285 elimination, 281 formulation, 282 metabolism, 281, 281f pregnancy/lactation risks, 720t structure, 280, 281f Amitriptyline, 386t burning mouth syndrome treatment, 675 dermatologic conditions, 395 Amlodipine anal fissure, calcium channel blockers, 361 bioavailability, 359 wound healing, 360 Ammonia, liver function tests, 686, 687t Ammonium lactate pregnancy/lactation risks, 724t xerosis treatment, 587 Amnesteem. see Isotretinoin Amoxicillin, 77 dosages, 73, 74t–75t pregnancy/lactation risks, 717t Amoxicillin–clavulanate, 77 Amoxicillin–sulbactam, 77 Amphotericin B, 482t systemic, pregnancy/lactation risks, 719t Amphotericin, pregnancy/lactation risks, 719t Ampicillin, 73 Amyopathic dermatomyositis, 400 ANA. see Antinuclear antibodies (ANA) Analgesics erosive gingivostomatitis treatment, 668 pregnancy/lactation risks, 717t recurrent aphthous stomatitis, 670 Analytic studies, 58 Anaphylaxis bacitracin, 468 intravenous immunoglobulin adverse reactions, 403 Androgen(s) attenuated. see Attenuated androgens clinical conditions, 367, 368f in females, 367 in males, 367 mechanism of action, 367–369 Androgen excess syndromes, systemic corticosteroids, 141 Androgenic alopecia, spironolactone, 376–377 Androgen inhibitors, 367b, 369t, 376–379 definition, 367 see also specific drugs. Androstenedione, 367

Anemia drug-induced immune hemolytic, 696–697 hemolytic. see Hemolytic anemia; drug-induced Anesthetics injectable, pediatric patients, 768–769 local. see Local anesthetics topical, 641–644 erosive gingivostomatitis, 668 xerostomia (dry mouth), 674 Angioedema, antihistamines, 356–357 Ankle–brachial blood pressure ratio (ankle– brachial index, ABI), 598 Anogenital area, contact dermatitis, 621–622 Anogenital warts (AGW) intralesional immunotherapy, 499 sinecathechin, 503 trichloroacetic acid, 501 Antacids, 90t drug interactions, rifamycins, 93t fluoroquinolones, 83t Antagonists definition, 5t drug receptors, 4–6, 5t receptors, 5t Anthracyclines, 407t, 415 indications, 408t see also specific drugs. Anthralin, topical, 628–629 pregnancy, 629 with topical corticosteroids, 518 Anthranilic acids, 454t Anthrax, tetracycline, 87 Antiacne medications see also specific drugs. Antiandrogens, 367b, 369–376, 369t definition, 369 see also specific drugs. Antiangiogenesis agents, 365 see also specific drugs. Antibacterial agents adverse reactions agranulocytosis, 691t pregnancy/lactation risks, 717t antifungal agents, 490–491 drug interactions, statins, 441t fluoroquinolones, 83t systemic, 70–73, 75–97 anti-inflammatory effects, 70 prevalence, 78 selection, 70 see also specific drugs. topical, 465 acne, 10041#s02225 advantages, 465 categories of, 465 hypoallergenic, 621 resistance, 472 rosacea, 472–478 wound care, 466–472 see also specific agents treatment, sulfur, 612 see also specific drugs.

789

Antibiotic interactions oral contraceptives, 380 warfarin, 740 Antibodies adalimumab, 296 botulinum toxin injections, 661 certolizumab pegol, 298 infliximab, 294 interleukin-12/23 inhibitor adverse reactions, 310 intravenous immunoglobulin therapy effects, 398 rituximab adverse reactions, 331 see also specific antibodies Antibody-dependent cellular cytotoxicity (ADCC), rituximab, 331 Anticancer agents, systemic, 406–418 see also specific drugs. Anticholinergic drugs, 446–447, 446t absorption, 446 doses, 446 toleration, 447 see also specific drugs. Anticipation. see Drug safety Anticoagulants, 80t, 90t drug interactions, rifamycins, 93t Anticoagulants, fluoroquinolones, 83t Anticonvulsants (aromatic), 80t drug interactions statins, 441t systemic retinoids, 258t thalidomide, 461t see also specific drugs. Antidepressants, 80t, 385 drug interactions fluoroquinolones, 83t statins, 441t for obsessive–compulsive disorder, 395 see also specific drugs. Antidrug antibodies (ADA) adalimumab, 296 biologic therapies, 324 certolizumab pegol, 298 infliximab, 294 Antidysrhythmic agents, 80t, 83t Antidysrhythmics, 83t drug interactions, rifamycins, 93t Antiepileptic drugs agranulocytosis, 691t see also specific drugs. Antifungal agents, systemic, 100–104, 113 children with superficial fungal infection, 108–110 contraindications, 108 drug interactions, 111 statins, 441t indications, 104–108, 104t–105t oral candidiasis, 668 mechanism of action, 103, 103f monitoring, 111–113 pediatric patients see also specific infections

790

Index

Antifungal agents, systemic (Continued) pharmacokinetic properties, 100–102, 101t systemic, pregnancy/lactation risks, 719t see also specific drugs. Antifungal agents, topical allylamines, 482t, 486–487 azoles, 481–486, 482t benzylamines, 482t, 486–487 ciclopirox olamine, 487–488 comparative studies candidiasis, 489–490 dermatophytes, 488–489 special properties, 490–491 feet contact dermatitis, 621 hypoallergenic, 620b in vitro and in vivo activity of, 483t polyenes, 481, 482t selenium sulfide, 488 sulfur, 612 tavaborole, 488 see also specific drugs. Antifungals, 80t Antigout meds, 80t Antihistamines anti-inflammatory action, 350 atopic dermatitis, 357 epinephrine, 646 first-generation, 349, 351–352, 351t indications, 351 pharmacology, 353t H1 antihistamines, 355 lactation, 355 pregnancy, 355 subsensitivity, 356 tachyphylaxis, 356 tolerance, 356 H2 antihistamines, drug interactions, 737t historical overview, 349–351 indications angioedema, 356–357 chronic autoimmune urticaria, 402 chronic urticaria, 356–357 as local anesthetics, 633t mechanism of action, 350–351 pregnancy/lactation risks, 720t receptor interactions, 5t second generation, 349–350, 352–354, 352t drug interactions, 355, 355t withdrawal, 66 sedation, 351–352 thalidomide, 461t see also specific drugs. Anti-idiotypic antibodies, 398 Anti-IL-12/23 therapy, 776 Anti-inflammatory agents antifungal agents, 490 antihistamines, 350 retinoids, 534 salicylic acid, 608 systemic antibacterial agents, 70 thalidomide, 458

Anti-inflammatory agents (Continued) xerostomia (dry mouth) treatment, 674 see also specific drugs. Anti-inflammatory effects, methotrexate, 159 Anti-inflammatory shampoos, 577t Antimalarial agents, 234–242, 235t absorption, 235–236 adverse effects, 239–241, 240b ocular effects, 240 pregnancy and lactation, 241 retinopathy, 239–240 benefits, 239–241 bioavailability, 235–236 contraindications, 239 drug interactions, 242, 243t excretion, 236 glucose-6-phosphate dehydrogenase, 30t indications, 236–238, 237b mechanism of action, 236 metabolism, 236 monitoring, 241–242, 242b off-label uses, 238–239 benign lymphocytic infiltrates, 238–239 granulomatous dermatoses, 238 panniculitis, 239 photodermatoses, 238 porphyria cutanea tarda, 238 psoriatic arthritis, 239 pharmacology, 235–236, 235t retinopathy, 15 structure, 235, 236f therapeutic guidelines, 242–243 treatment, 242–243 see also specific drugs. Antimalarial drugs, hematologic toxicity, 696 Antimetabolites, 211–214, 407t, 416–417 hydroxyurea, 213–214 indications, 408t malignancy induction, 701t, 706 thioguanine, 211–212 see also specific drugs. Antimicrobials, 577t cephalosporins, 75 clofazimine, 449 xerostomia (dry mouth) treatment, 674 see also specific drugs. Antimicrotubule agents, 407t, 414–415 indications, 408t see also specific drugs. Antimitotic shampoos, 577t Antineutrophil cytoplasmic antibodyassociated vasculitis, 399–403 Antinuclear antibodies (ANA), tumor necrosis factor inhibitor adverse reactions, 300 Antioxidants, topical, 624–626, 625t see also specific antioxidants Antiparasitic agents, systemic, 126–131 albendazole adverse effects, 129 dosing, 129t drug interactions, 129 indications, 129

Antiparasitic agents, systemic (Continued) mechanism of action, 128 pharmacology, 128 pregnancy, 129 resistance, 129 therapeutic guidelines, 129 doxycycline, 130–131 ivermectin, 126–128 adverse effects, 127–128 drug interactions, 128 indications, 127 lactation, 128 mechanism of action, 127 pharmacology, 127 resistance, 128 risks, 128b teratogenic effects, 128 therapeutic guidelines, 127 pharmacology, 131t thiabendazole, 129–130 adverse effects, 130 dosing, 130t drug interactions, 130 indications, 130 mechanism of action, 130 pharmacology, 129–130 pregnancy, 130 resistance, 130 therapeutic guidelines, 130t Antiparasitic drugs, sulfur, 612 Antiparasitic drugs, systemic see also specific drugs. Antiparasitic drugs, topical, 504–509 indications larva migrans, 509 pediculoses, 506 scabies, 506 see also specific drugs. Antiphospholipid antibody syndrome aspirin, 363 ulcers, 599t–600t Antiplatelet agents, 359–365 see also specific drugs. Antiproliferative effects corticosteroid adverse reactions, 515–516, 515b shampoos, 577t tar, 613 Antipsychotic agents, 80t fluoroquinolones, 83t Antipsychotic drugs agranulocytosis, 691t atypical, 393–394 see also specific drugs. Antiretroviral drugs drug interactions, statins, 441t see also specific drugs. Antiseptics, 478–479 Antiseptics, topical see also specific agents Anti-thyroid drugs, agranulocytosis, 691t

Index

Antituberculosis agent interactions, statins, 441t Antiviral agents see also specific drugs. Antiviral agents, systemic, 115–124 human herpes virus infections, 115–123, 115t human immunodeficiency virus vaccine development, 124 mechanism, 117f off-label uses, 118–119 see also specific drugs. Antiviral agents, topical, 494–503, 494b, 495t cytodestructive drugs, 499–503 immune-enhancing drugs, 498–499 virucidal drugs, 494–497 see also specific drugs. Anxiety, 384–385 management, 384–385 Aphthous stomatitis etanercept, 291 thalidomide, 460 API (active pharmaceutical ingredients), 762 Aplastic anemia (pancytopenia) drug-induced, 691t trimethoprim–sulfamethoxazole, 696 Apoptosis, 273 aminolevulinic acid, 282 corticosteroids, systemic, 139 Approval process. see Drug approval process Apremilast, 201–202 adverse effects, 201–202 contraindications, 201–202 depression, 202 drug interactions, 202t gastrointestinal effects, 201 indications, 201, 201b off-label uses, 201 pharmacokinetics, 201 pharmacology, 201 pregnancy/lactation risks, 723t suicide risk, 202 Aqueous components, compounding, 762 ARAT (acyl CoA-retinol acyltransferase), 532 ARBITER 6-HALTS, ezetimibe, 443 5α Reductase, 367, 367b Arsenic trioxide (ATO), 427 Artefill, 652t Arterial Biology, 443 Arterial ulcers, 598, 599t–600t Arthritis psoriatic. see Psoriatic arthritis rheumatoid. see Rheumatoid arthritis Arylpropionic acids, 454t Aspartate aminotransferase. see AST/ALT Aspergillosis, tumor necrosis factor inhibitor, 299 Aspirin, 362–363 adverse reactions implantation block, 712 pregnancy/lactation risks, 713t

Aspirin (Continued) indications mastocytosis, 455 urticaria, 455 Assessment algorithm, malignancy induction, 701t–702t AST/ALT, liver function tests, 686, 687t Astemizole, withdrawal, 65, 65t Atheroemboli, 599t–600t Atopic dermatitis, 357 cyclosporine, 191 treatment corticosteroids, 516–517 intravenous immunoglobulin, 402 narrowband UVB phototherapy, 267 pimecrolimus, 553 systemic tacrolimus, 553 tacrolimus, 550 tacrolimus maintenance therapy, 550 UVA-1 phototherapy, 269 Atorvastatin, 436 dose, 440t drug interactions, 441t, 739 pharmacology, 440t structure, 437f–438f Atrial fibrillation, bisphosphonate adverse reactions, 434 Atrophia blanche. see Livedoid vasculopathy (atrophia blanche) treatment Atrophie blanche, 399 Atrophogenic effects, corticosteroid adverse reactions, 515–516 Atrophy, corticosteroid adverse reactions, 519b, 520 Attenuated androgens, 447 doses, 447 off-label uses, 447 Atypical antipsychotic agents, 393–394 see also specific drugs. Atypical fractures, bisphosphonate adverse reactions, 434 Atypical mycobacterial infections, tetracyclines, 87 Autoimmune connective tissue diseases, 162 azathioprine, 173 rituximab, 331 Autoimmune dermatoses treatment, extracorporeal photochemotherapy, 273–274, 278 Autoimmune diseases/disorders malignancy induction, 704–705 tetracycline adverse reactions, 88 tumor necrosis factor inhibitor adverse reactions, 300 see also specific diseases/disorders Autoimmune urticaria, chronic. see Chronic autoimmune urticaria Avascular necrosis (AVN) (osteonecrosis), corticosteroid-treated pediatric patients, 771 AVN, corticosteroid-treated pediatric patients, 771

791

Avobenzone (butylmethoxydibenzoylmethane) structure, 568f sunscreens, 567–568, 567t AVSE (acute vestibular side effects), tetracyclines, 87 Azalides, 78, 80t pregnancy/lactation risks, 717t see also specific drugs. Azaribine, withdrawal, 65t Azasan. see Azathioprine Azathioprine (AZA), 169–176, 400–401, 769t absorption, 170 adverse effects, 173–176, 174b fertility, 174–175 gastrointestinal effects, 175 hepatic effects, 176 immunosuppression carcinogenesis, 173–174 infection risk, 174 lactation, 174–175 myelosuppression, 174 pregnancy, 174–175 vaccinations, 174 adverse reactions contraceptive failure, 712, 712t hematologic toxicity, 692 hepatotoxicity, 686t malignancy induction, 692, 701t, 703–704 pancytopenia, 16 pregnancy/lactation risks, 713t thrombocytopenia, 694 contraindications, 173 distribution, 170 dosing, 172 drug interactions, 175t, 176, 694, 738 excretion, 170–171 indications, 172b erosive gingivostomatitis, 667 mechanism of action, 172 metabolism, 28f, 170–171 thiopurine methyltransferase, 28–29 see also Thiopurine methyltransferase (TMPT). monitoring, 176, 176b off-label uses, 172–173 pediatric patients adverse effects and monitoring, 774 dosage, 774 pharmacology, 170–172, 170t, 171f polymorphism testing, 31 pregnancy/lactation risks, 722t–723t synthesis, 169 Azelaic acid acne vulgaris, 473t, 477 adverse effects, 477 microbiologic activity, 477 patch testing, 468t perioral dermatitis, 477 pharmacology, 477 pigmentation disorders, 477

792

Index

Azelaic acid (Continued) plaque psoriasis, 477 pregnancy categories, 474t pregnancy/lactation risks, 718t rosacea, 473t, 477 Azithromycin adverse reactions, 79 pregnancy/lactation risks, 717t antimicrobial activity, 78 dosages, 81 drug interactions, 79–81 indications, 78–79 Azole antifungals, drug interactions, 737 Azoles, 481–486, 482t anti-inflammatory properties, 490 drug interactions statins, 441t in vitro and in vivo activity of, 483t topical see also specific drugs.

B Bacillus-Calmette-Guerin (BCG), 776 Bacillus polymyxa, 468 Bacitracin adverse effects, 468 bacterial coverage, 467t dermatologic uses, 466–468 drugs used for wound care and minor, 466–472 mechanism of action, 467t microbiologic activity, 466 patch testing, 468t pharmacology, 466 pregnancy categories, 468t pregnancy/lactation risks, 718t for wound care and minor topical antibacterial infections, 467t Bacterial conjunctivitis, systemic retinoid adverse reactions, 257 Bacterial counts, chronic wound care, 600–601 Bacterial infections ulcers, 599t–600t see also specific infections Baker–Gordon chemical peel, 593t, 594 Baricitinib, 207 Bartonella infections, rifamycin treatment, 91 Basal cell carcinoma (BCC), 420 drug-induced, 708t treatment, photodynamic therapy, 284 ulcers, 599t–600t Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT) trial, 422–423 Baseline laboratory tests, 14–15 β-blockers, 361–362, 362b, 772–773 drug interactions, epinephrine, 646 see also specific drugs. BCC. see Basal cell carcinoma (BCC) B cell(s) lymphoma. see Cutaneous B-cell lymphoma rituximab effects, 331 Becaplermin, off-label use, 628

Beeson–McCollough chemical peel, 594 Behçet’s disease treatment corticosteroids, 518 etanercept, 291 Benacort-Tetrastat (Mary’s magic Mouthwash), mucositis (stomatitis), 672 Benefits–risks, labeling, 63 Benign intracranial hypertension, tetracycline effects, 87–88 Benign lymphocytic infiltrates, antimalarial agents, 238–239 Benign prostate hypertrophy (BPH), dutasteride treatment, 378 Benoxaprofen withdrawal, 64t, 678t Benzocaine, 633t, 643 structure, 634f Benzodiazepines, 80t antifungals, 737 drug interactions, rifamycins, 93t thalidomide, 461t Benzophenones, neck contact dermatitis, 620 Benzoyl peroxide (BP) acne vulgaris, 473t for acne vulgaris, 472–474 formulations, 474t patch testing, 468t pregnancy categories, 474t pregnancy/lactation risks, 718t rosacea, 473t, 474 Benzyl alcohol, eyelid contact dermatitis, 619 Benzylamines, 482t, 486–487 in vitro and in vivo activity of, 483t see also specific agents Benzyl benzoate, 508 formulations, 505t Beta lactams see also specific drugs. Betamethasone indications nail psoriasis, 561 scalp psoriasis, 561 with topical calcipotriene, 561 Bevacizumab, psoriasis, 365 Beverages, 83t Bexarotene, 246, 435, 535–536 absorption, 435 adverse reactions, 435 teratogenicity, 713t bioavailability, 435 cell cycle effects, 535 contraindications, 435 drug interactions, 435, 535 excretion, 435 indications, 250, 435, 536t cutaneous T-cell lymphoma, 536, 538 mechanism of action, 435, 529, 530t–531t structure, 530f metabolism, 435 monitoring, 259b, 435 pharmacology, 247t, 435, 531t precautions, 435, 535t structure, 435

β-hydroxy acids, 593 see also specific types Bifonazole, anti-inflammatory properties, 490 Bile acid sequestrants, 90t Biliary excretion, pharmacokinetics, 8 Bilirubin, liver function tests, 686, 687t Bimatoprost, 628 Bioactivation definition, 3t hepatic drug metabolism, 679 Bioavailability α-hydroxy acids formulations, 589–590 aminolevulinic acid, 280–281 methyl aminolevulinate, 280–281 pharmacokinetics, 2t, 8–9 psoralens, 264 Bioequivalence, 3t Biofilms, delayed onset, 655 Biologic agents, 302–303, 311 adverse reactions, malignancy induction, 701t immunological safety, 302–303 indications, recurrent aphthous stomatitis, 671 legislation, 52 with systemic retinoid, 250 see also specific drugs. Biologic plausibility, malignancy induction, 702t Biologic therapies, 775 Biotin, 446t, 447–448 Biotransformation definition, 3t hepatic drug metabolism, 679 Bis-ethylhexyloxyphenol methoxyphenol triazine, 570t Bisphosphonates, 431–434, 432t absorption, 431 administration, 431 adverse reactions, 433–434 bioavailability, 431 contraindications, 433 drug interactions, 434 excretion, 431 indications, 432–433 mechanism of action, 431–432 metabolism, 431 monitoring, 434 pharmacology, 431–432 pregnancy, 433 structure, 431, 431f therapeutic guidelines, 434 see also specific drugs. Bituminous tar, 613 Bladder cancer, drug-induced alkylating agents, 705–706 prevention/detection, 708t Bleomycin, 495t, 499–500 adverse reactions, pregnancy/lactation risks, 713t Blepharoconjunctivitis, 257 β-Blockers, 80t, 83t

Index

Blood–brain barrier definition, 3t distribution effects, 2 Blood donation, dutasteride, 377–378 BMS (burning mouth syndrome), 674–675 Body weight, distribution effects, 3 Bone density, methotrexate in pediatric patients, 774 Bone, systemic retinoid adverse reactions, 254b, 256–257 Botulinum toxin injections, 656–664, 662t activity determination, 658 adverse reactions, 661–662 contraindications, 661, 661b follow-up, 664 history, 656–664 indications, 660 facial rhytides, 660–661 hyperhidrosis, 661, 662t mechanism of action, 657–658 nerve conduction, 658f neuromuscular recovery, 657 patient evaluation, 660 pharmacology, 657–660 products, 658–660 reconstitution, 658, 660t serotypes, 657 structure, 657, 658f techniques, 661–662 Botulism, 656–657 Bowel obstruction and perforation, rituximab, 336 Bowel perforation, 143 Boxed Warnings, labeling, 63 BPH (benign prostate hypertrophy), dutasteride treatment, 378 BRAF inhibitors, 407t, 418 indications, 408t B-rapidly-accelerated fibrosarcoma (B-RAF), 424 Breast cancer finasteride, 377 Breastfeeding and menses effects, 424 Briakinumab (ABT-874), 303, 305, 309, 311 adverse effects, 309 clinical trials, 309 efficacy, 303 Brimonidine, 629 pregnancy/lactation risks, 718t Brodalumab dermatologic indications, 317 dosage, 318t efficacy outcomes, 318t off-label uses, 318 pharmacology, 317 plaque psoriasis, 317 pregnancy/lactation risks, 723t safety and monitoring guidelines, 318 Brody peel, 594 Bromfenac, withdrawal, 678t

Bromfenac, withdrawal of, 64t Bronchodilator interactions see also specific drugs. Bronchodilators interactions fluoroquinolones, 83t Bruising, phytonadione (vitamin K), 627 Bullous dermatoses treatment corticosteroids, 518 niacinamide, 453 rituximab, 331 Bullous pemphigoid antigen 1 (BPAG1), 400 Bullous pemphigoid antigen 2 (BPAG2), 400 Bullous pemphigoid, systemic corticosteroids, 139–140 Bullous pemphigoid treatment corticosteroids, 400 intravenous immunoglobulin, 400 rituximab, 331b, 334–335 Bupivacaine, 633t bioavailability, 632 pharmacology, 635t pregnancy/lactation risks, 717t therapeutic guidelines, 640–641 Bupropion, 386t, 390–391 Burning mouth syndrome (BMS), 674–675 Burns, mupirocin, 470 Buspirone, anxiety, 385 Butazones, aplastic anemia, 691t Butenafine, 482t, 487 Butylmethoxydibenzoylmethane. see Avobenzone (butylmethoxydibenzoylmethane)

C Calcineurin inhibitors, 6t, 80t drug interactions rifamycins, 93t malignancy induction, 701t, 706 statin interactions, 441t Calcineurin inhibitors, topical, 549–556 see also specific agents Calcinosis cutis, calcium channel blockers, 359–360 Calcipotriene pregnancy/lactation risks, 723t receptor interactions, 5t structure, 560f Calcipotriene, topical, 559, 559t high-dose, 561 indications, 559, 561b intertriginous psoriasis, 561 nail psoriasis, 561 pediatric psoriasis, 561 plaque psoriasis, 560–561 pustular psoriasis, 561 scalp psoriasis, 561 with topical betamethasone, 561 with topical corticosteroids, 518 Calcitriol, 560, 562 psoriasis, 562

793

Calcium bisphosphonate adverse reactions, 433–434 pharmacodynamics, 7 Calcium channel blockers (CCBs), 80t, 359–361 adverse reactions, 361 bioavailability, 359 drug interactions, 737t grapefruit juice, 738–739 statins, 441t indications, 361b mechanism of action, 359, 360f off-label uses, 359–361, 360b pharmacology, 359 therapeutic guidelines, 361 Calcium hydroxyapatite, 651 Calculus, dental, 666 Calluses, salicylic acid, 608–609 Cancers tumor necrosis factor inhibitor adverse reactions, 299 see also Carcinogenesis; Malignancy induction see also specific cancers Candidiasis, 489–490 interleukin 17 inhibitors, 318 oral, 668–669 tumor necrosis factor inhibitor adverse reactions, 299 Cantharidin, 501–502 Capecitabine, 407t, 417 adverse reactions, 410t indications, 408t Capillary leak syndrome, denileukin diftitox adverse reactions, 416 Capsaicin, 628, 633t, 645t, 647–648 contraindications, 648b indications, 647 mechanism of action, 635t off-label use, 647 Carbamazepine adverse reactions aplastic anemia (pancytopenia), 691t hepatotoxicity, 681t HLA markers, 31t label warning, 31 pimozide interactions, 740 Carbapenems, 70 Carboplatin, 407t, 414 adverse reactions, 410t indications, 408t Carcinogenesis, 231, 706 tar, 613–614 see also Malignancy induction. Carcinogenicity, photodynamic therapy, 285 Carcinoid tumors, niacinamide, 453 Cardiac arrhythmias, drug withdrawals, 65t Cardiotoxicity doxepin, 386–387 pimozide, 393 treatment, chemical peels, 596

794

Index

Cardiovascular system drug withdrawals, 65t injectable local anesthetic toxicity, 639 Caregivers, adherence effects, 38 Cartilage formation, fluoroquinolones, 82 Carvedilol, 362 flushing, 362 Case–control studies, 59t Case–crossover studies, 59t Case reports, 59t malignancy induction drug assessment, 703 Case series, 59t Castor oil, 762t Cataracts, PUVA therapy, 16 Causality assessment, drug safety, 60t CCBs. see Calcium channel blockers (CCBs) CCL20, psoriasis, 288 Cefaclor, 76t adverse reactions, pregnancy/lactation risks, 717t Cefadroxil, 76t Cefazolin, 76t Cefdinir, 76t pregnancy/lactation risks, 717t Cefditoren, 76t Cefepime, 76t Cefixime, 76t Cefotaxime, 76t Cefotetan, 76t Cefoxitin, 76t Cefpodoxime, 76t Cefprozil, 76t Ceftaroline, 76t Ceftazidime, 76t Ceftibuten, 76t Ceftobiprole, 75 Ceftriaxone, 76t Cefuroxime, 76t Cefuroxime axetil, 76t Cell cycle, bexarotene effects, 535 Cell surface drug receptors, 4 Cellular targets, hepatotoxicity mechanisms, 681t Central nervous system (CNS) epinephrine adverse reactions, 646 fluoroquinolone effects, 81 injectable local anesthetic toxicity, 638 systemic retinoid adverse reactions, 257 Cephalexin, 76t pediatric dosing, 769t pregnancy/lactation risks, 717t Cephalosporins, 75–77, 76t adverse reactions, 76–77 pregnancy/lactation risks, 717t antimicrobial activity, 75 dosage, 71t–72t, 77 drug interactions, 77 fifth generation, 75, 76t first generation, 76t fourth generation, 76t indications, 76 pharmacokinetics, 75–76

Cephalosporins (Continued) pharmacology, 75–76 second generation, 76t third generation, 76t see also specific drugs. Cerivastatin interactions, 739 Certolizumab pegol (CZP) adverse effects, 297–298 biosimilars, 298 contraindications, 297, 298b drug interactions, 298 indications, 297 psoriasis, 297 monitoring guidelines, 298 off-label uses, 297 therapeutic guidelines, 298 Cetirizine, 352t, 354 pregnancy/lactation risks, 720t Cetuximab, 406, 407t adverse reactions, 409t indications, 406, 408t Cevimeline, xerostomia (dry mouth), 674 Challenge hepatotoxicity diagnosis, 685 malignancy induction, 702, 702t Chemical peels, 592–593, 593t adverse reactions, 595b contraindications, 595b deep, 593t–594t, 594–596 frosting patterns, 593t historical aspects, 592 indications, 594–595, 595b ingredients, 593t mechanism of action, 592 medium-depth, 593–594 pregnancy, 596 salicylic acid, 609 superficial, 592–593 see also specific types Chemical stabilizers, corticosteroid vehicle, 514 Chemokine receptor antagonists see also specific drugs. Chemotherapeutic agents. see Cytotoxic agents Chickenpox, 118 Chilblains, calcium channel blockers, 359 Children, photodynamic therapy, 285 Chlorambucil, 218–220, 400 adverse reactions hematologic toxicity, 694 malignancy induction, 694, 701t, 705–706 Chloramphenicol, aplastic anemia, 692t Chlorhexidine, 478t, 479 Chlorhexidine gluconate oral rinse acute necrotizing ulcerative gingivostomatitis, 671 xerostomia (dry mouth) treatment, 674 Chloroprocaine, pregnancy/lactation risks, 717t Chloroquine, 402 Chlorpheniramine, pregnancy/lactation risks, 720t

Cholecalciferol. see Vitamin D3 Cholestasis, hepatotoxicity, 678, 684t Cholesterol, 436 Chronic anal fissure, calcium channel blockers, 361 Chronic autoimmune urticaria antihistamines, 402 intravenous immunoglobulin, 402 Chronic eczema, systemic retinoids, 252 Chronic idiopathic urticaria adverse effects, 192–193, 192b contraindications, 192 cyclosporine, 192 drug interactions, 193, 194t hyperlipidemia, 193 hypertension, 192–193 malignancy risk, 193 monitoring, 193–194, 195b renal effects, 192 Stevens–Johnson Syndrome, 192 therapeutic guidelines, 194–197 toxic epidermal necrolysis, 192 Chronic leg ulcers, contact dermatitis, 622 Chronic plaque psoriasis, anthralin, 629 Chronic urticaria, antihistamines, 356–357 Chronic wound care, 598, 599t–600t, 601–605 laboratory examination, 600–601 medical history, 598 physical examination, 598 social history, 598 surgical history, 598 system review, 598 wound history, 598 Chrysotherapy. see Gold Churg-Strauss syndrome, 399 Cicatricial pemphigoid, 401 Cicatricial pemphigoid treatment corticosteroids, 402 intravenous immunoglobulin, 402 rituximab, 331 Ciclopirox, 482t pregnancy/lactation risks, 719t shampoos, 577t, 578 therapeutic guidelines, 582–583 Ciclopirox olamine, 487–488 anti-inflammatory properties, 490 Cidofovir, 495t, 496–497 pregnancy/lactation risks, 721t Cimetidine, 375 adverse reactions hepatotoxicity, 686t thrombocytopenia, drug-induced, 692t pediatric dosing, 769t Cinoxate, sunscreens, 567t Ciprofloxacin, pregnancy/lactation risks, 717t CIR (Cosmetic Ingredient Review), á-hydroxy acids, 590 Circulating antibodies and receptors, intravenous immunoglobulin therapy effects, 398 Circulation, distribution effects, 2

Index

Cisapride, withdrawal, 65t Cisplatin, 407t, 414 adverse reactions, 410t indications, 408t Citalopram, 388, 388t, 391t Claravis. see Isotretinoin Clarithromycin, 78 adverse reactions, 79 antimicrobial activity, 78 dosages, 71t–72t, 81 macrolide interactions, 740 Clavulanate, amoxicillin with. see Amoxicillinclavulanate Clearance schedule, PUVA, 265–266 Clindamycin, 95 acne vulgaris, 473t, 475 acute necrotizing ulcerative gingivostomatitis, 671 adverse effects, 475 dosage, 71t–72t, 96 microbiologic activity, 474–475 patch testing, 468t pediatric dosing, 769t pharmacology, 474–475 pregnancy categories, 474t pregnancy/lactation risks, 96, 717t rosacea, 473t Clinical Studies section, labeling, 63 Clinical trials, 59t hepatotoxicity information dissemination, 683 Clobetasol propionate anti-inflammatory shampoos, 577t potency, 513t structure, 513f therapeutic guidelines, 583 with topical corticosteroids, 518 Clodronate, 431 Clofazimine, 446t, 448–450, 448t absorption, 448–449 adverse reactions, 450 drug interactions, 450 historical aspects, 448 indications, 449 mechanism of action, 449, 449t monitoring guidelines, 450 off-label uses, 449–450 pharmacology, 448–449, 448t Clomipramine, agranulocytosis, 691t Clonazepam, burning mouth syndrome, 675 Clostridium botulinum, 656–657 Clostridium difficile-associated disease, 96–97 Clotrimazole, 482t adverse effects, 484 candidiasis, 10042#p1045 indications, 483 pharmacology, 483 pregnancy/lactation risks, 719t CNS. see Central nervous system (CNS) Coagulation reactions, metabolism, 7–8 Coagulation, wound healing, 598 Coal tar, 613, 613t pregnancy/lactation risks, 723t

Cocaine, absorption, 633t Codeine, pregnancy/lactation risks, 717t Coenzyme Q10, drug interactions, 739t Cohort studies, 58, 59t Colchicine, 401, 446t, 450–452 adverse reactions, 451 pregnancy/lactation risks, 713t contraindications, 451b drug interactions, 451–452, 452t, 738 hematologic toxicity, 696–697 indications, 451b recurrent aphthous stomatitis, 10040#u1495 monitoring guidelines, 452 off-label uses, 450–451 overdose, 451–452 pharmacology, 448t, 450 structure, 450f Coleman peel, 594 Collagen(s), as filler, 650–651, 652t Collagen type I, α-hydroxy acids effects, 586 Colloidal sulfur, 611, 611t Combination pill, oral contraceptives, 379 Combination products, legislation, 53 Combination therapy PUVA, 266 rituximab, 331 see also specific therapies Community-acquired MRSA (CA-MRSA), 474–475 Compassionate use regulations, drug approval process, 52 Complement, intravenous immunoglobulin therapy effects, 398 Complement-mediated cytolysis, rituximab, 332 Compliance. see Adherence Compounding, 759–766 clinical evidence, 761–762 compounding triad, 760–761, 760f controversy, 760 cream and ointment bases, 762, 763t definition, 760 drug treatment history, 760–761 excipients, 762–764 feasibility, 762–764 formula instructions, 764 goals, 760 historical aspects, 759 ingredients, 762 levigating agents, 762t off-label use, 761 preparations, 765, 765b mixing technology, 765 prescription writing, 761 stable formulation, 761–764 tar, 613 see also specific agents; specific agents Concentration, percutaneous absorption, 9t Concern, thresholds of, drug safety, 18

795

Condylomata acuminata (genital warts) treatment cidofovir, 496 imiquimod, 498 podofilox, 501 Congestive heart failure, tumor necrosis factor inhibitor adverse reactions, 300 Conjugation reactions hepatic drug metabolism, 679b metabolism, 7–8 Conjunctivitis, bacterial, systemic retinoid adverse reactions, 257 Consent. see Informed consent Consent forms, 755–756 Contact allergens, topical see also specific agents Contact allergy polymyxin B, 468 salicylic acid adverse reactions, 611 tar adverse reactions, 614 as treatment. see Contact allergens; topical Contact dermatitis, 617–618 allergic. see Allergic contact dermatitis (ACD) anogenital area, 621–622 chronic leg ulcers, 622 eyelids, 619 face, 619 feet, 621 hands, 620–621 irritant. see Irritant contact dermatitis (ICD) lips, 619–620 neck, 620 perioral region, 619–620 photoallergic, neck, 620 regional approach, 618–622 see also specific anatomical features scalp, 618–619 stasis dermatitis, 622 suspicion of, 618–622 treatment pimecrolimus, 555 tacrolimus, 552 Contact sensitivity, calcium channel blockers adverse reactions, 361 Contact urticaria, sunscreen adverse reactions, 572 Contraceptives. see Hormonal contraceptives Contraindications section, labeling, 63 Cornea, systemic retinoid adverse reactions, 257 Corticosteroid(s) adverse reactions, cataracts, 19 cross-reactions, 621t enzyme inhibition, 6t indications bullous pemphigoid, 400 cicatricial pemphigoid, 402 erosive gingivostomatitis, 667 pemphigoid gestationis (herpes gestationis), 401

796

Index

Corticosteroid(s) (Continued) pemphigus foliaceus, 400 systemic lupus erythematosus, 402 toxic epidermal necrolysis, 402 intralesional erosive gingivostomatitis, 668 recurrent aphthous stomatitis, 670 intravenous immunoglobulin therapy effects, 398 monitoring, 17 osteonecrosis. see below osteoporosis. see Corticosteroid-induced osteoporosis peptic ulcer disease (PUD), 443–444 receptor interactions, 5t systemic. see below topical recurrent aphthous stomatitis, 670. , see below transcription factors, 7 see also Glucocorticoid(s). Corticosteroid-induced osteonecrosis diagnostic tests, 17 management, 19 Corticosteroid-induced osteoporosis prevalence, 431 prevention, 435b treatment, 431–432 bisphosphonates. see Bisphosphonates Corticosteroids, 83t Corticosteroids, systemic, 134–155 absorption and distribution, 135, 135b acute dermatitis, 140–141 adverse effects, 142–148, 143b androgen excess syndromes, 141 apoptosis, 139 bullous pemphigoid, 139–140 dosing, 142 drug interactions, 151, 152t excretion, 135–136, 136t exfoliative erythroderma, 141 glucocorticoid effects, 137, 138t Herpes Zoster, 141 hypothalamic-pituitary-adrenal-axis function, 137 hypothalamic-pituitary-adrenal-axis suppression, 141–142 indications, 139–141, 139b intramuscular administration, 141–142 mechanism of action, 136–139, 136t metabolism, 135–136, 136t mineralocorticoid effects, 137 monitoring, 151, 153b off-label uses, 139–141 osteonecrosis. see Corticosteroid-induced osteonecrosis osteoporosis. see Corticosteroid-induced osteoporosis paediatric patients adverse effects and preventive strategies, 771–772

Corticosteroids, systemic (Continued) general principles, 771 tapering systemic corticosteroids, 772 pemphigus vulgaris, 139–141 pharmacology, 134–155, 134t postherpetic neuralgia, 141 pregnancy risk, 144 pulse intravenous administration, 142 shampoos, 578 Stevens–Johnson Syndrome, 140 structure, 134–135, 135f therapeutic guidelines, 151–155, 153b toxic epidermal necrolysis, 140 transcription factors, 137–139, 138f see also specific drugs. Corticosteroids, topical, 512–514 absorption, 580–581 adverse reactions, systemic, 519–520, 519b risk factors, 519–520, 519b adverse reactions, topical, 520–522 addiction, 520 allergic contact dermatitis, 521, 521b atrophy, 519b, 520 ocular effects, 520 perioral dermatitis, 520 pregnancy/lactation risks, 520 rebound syndrome, 520 tachyphylaxis, 521 vehicle-related adverse reactions, 522, 522t with clobetasol propionate, 518 compounding, 522–523 contraindications, 516, 516b indications, 516–519, 516b allergies, 620b alopecia areata, 518 atopic dermatitis, 516–517 Behçet’s disease, 518 bullous dermatoses, 518 discoid lupus erythematosus, 517 erosive pustular dermatoses, 518 granuloma annulare, 517 hand contact dermatitis, 620 lichen planus, 517 lichen sclerosus et atrophicus, 517 melasma, 519 mouth rinses, 666 patch-stage cutaneous T-cell lymphoma, 518 psoriasis, 517–518 pyoderma gangrenosum, 518 scalp psoriasis, 517 seborrheic dermatitis, 518 vitiligo, 519 Well’s syndrome, 518 mechanism of action, 514–516 anti-inflammatory effects, 514–515, 515b antiproliferative actions, 515–516, 515b atrophogenic effects, 515–516 patient instructions, 523–527, 527b pharmacokinetics, 512–516

Corticosteroids, topical (Continued) pharmacology, 512–516 potency estimation, 512, 512b preparation choice, 522 with PUVA, 517–518 skin condition effects, 514 Stoughton Vasoconstrictor Assay, 512 structure, 512–514, 513f supervision, 523–527 systemic effects, 516 therapeutic guidelines, 522–527 with topical vitamin D, 562 trade names, 522, 522t vehicle-related issues, 514 with vitamin D, 517 see also specific types Corticosteroid withdrawal syndrome, 149–150 Cortisol (hydrocortisone) potency, 513t structure, 513f Cosmetic Ingredient Review (CIR), α-hydroxy acids, 590 Cosmetic therapy, sunscreens, 572 Cosmoderm, 651 Cosmoplast, 651 Cost(s) adherence effects, 34 see also Pharmacoeconomics Cost analyses. see Pharmacoeconomics; specific cost analyses Co-trimoxazole. see Trimethoprim– sulfamethoxazole (TMP-SMX) Cottonseed oil, 762t CQ. see Chloroquine CRABP (cystolic all-trans retinoic acid binding protein), 248 CRAMP (cystolic all-trans retinoic acid binding protein), 532 Cream and ointment bases, compounding, 762, 763t Creams, percutaneous absorption, 10t Crisaborole, pregnancy/lactation risks, 721t Crohn’s disease malignancy induction, 704 tacrolimus, 552 Cross-sectional studies, 59t Cross tolerance, 5t Crotamiton, 508 formulations, 505t pregnancy/lactation risks, 721t Crusting, photodynamic therapy adverse reactions, 285 Cryofibrinogenemia, attenuated androgens, 447 Cryotherapy, actinic keratoses, 285–286 CTCL. see Cutaneous T-cell lymphoma (CTCL) Cushing’s syndrome, 519 Cutaneous B-cell lymphoma, rituximab treatment, 331, 335 Cutaneous Crohn’s disease, tacrolimus, 552

Index

Cutaneous infections macrolides, 78–79 see also specific infections Cutaneous leishmaniasis, rifamycins, 91 Cutaneous lupus erythematosus treatment pimecrolimus, 555 rituximab, 331b, 335 Cutaneous sensory disorders, 383 Cutaneous T-cell lymphoma (CTCL) central hypothyroidism, 435 see also Thyroid replacement therapy. patch-stage, 518 pralatrexate, 416–417 treatment bexarotene, 536 corticosteroids, 518 extracorporeal photochemotherapy, 273, 274b, 275 PUVA, 265 retinoids, 538 systemic retinoids, 251 Cutaneous ulcers, metronidazole, 477 Cyclic AMP, pharmacodynamics, 7 Cyclooxygenase-2 (COX-2) inhibitors, adverse reactions, 57 Cyclophosphamide, 214–218, 400–401 adverse reactions hematologic toxicity, 694 malignancy induction, 694, 701t Cyclosporine (CSA), 187–198, 400, 402 absorption, 22t, 188 adverse effects and monitoring, 774–775 adverse reactions hyperlipidemia, 436 hypertension, 361 malignancy induction, 703–706 atopic dermatitis, 191 bioavailability, 188 chronic idiopathic urticaria, 192 drug interactions, 738 systemic retinoids, 258t excretion, 188 indication, 190, 191b erosive gingivostomatitis, 667 mouth rinses, 667 mechanism for action enzyme inhibition, 6t mechanism of action, 188–190, 189t metabolism, 188 monitoring, 17 off-label uses, 190–192 pediatric patients, 774–775 dosing, 774 pharmacology, 188–190, 188t pregnancy/lactation risks, 722t–723t psoriasis, 190 pyoderma gangrenosum, 192 Cyclosporine-induced hypertension, calcium channel blockers, 361 CYP. see Cytochrome P-450 (CYP)

CYP3A4 dutasteride, 379 finasteride, 378 injectable local anesthetics, 640 Cyproheptadine, 352, 352t Cyproterone acetate, 367, 373 Cystolic all-trans retinoic acid binding protein (CRABP), 248, 532 Cytochrome P-450 (CYP), 22–23 CYP1A2 drug interactions, 732, 732b polymorphisms, 680t CYP3A4, 23, 24t drug interactions, 733 inducers, 734b induction, 733–734 inhibitors, 734–735, 734b loss of efficacy, 733–734 polymorphisms, 680t substrates, 735b toxicity, 734 CYP1AD6, drug interactions, 10066#p01200 CYP3A5, drug interactions, 733 CYP2C9, 24–25 drug interactions, 732, 733b polymorphisms, 679, 741t CYP2C19, 25 allelic variants, 25 drug interactions, 732, 732b ketoconazole inhibition, 25 polymorphisms, 679, 741t population variability, 25t prevalence, 25t CYP2D6, 23t, 25–26 alleles, 25–26 drug interactions, 732–733, 734b gene duplication, 26 polymorphisms, 7, 679, 741t population frequency, 26t testing for, 26 CYP2E1, polymorphisms, 680t drug interactions, 15, 730–735 isoforms, 731–733 preclinical testing, 731 predictive testing limitations, 732 rifampin, 91 rifamycin, 92 in vitro studies, 730–731 in vivo studies, 730–731 see also specific isoforms drug withdrawals, 66 inducers, 681t hepatotoxicity mechanisms, 681t information sources, 26 inhibitors, 681t metabolism, 7–8 nomenclature, 22 polymorphisms, 23, 23t, 679 activity, 727t drug effects, 23 drug interactions, 726

797

Cytochrome P-450 (CYP) (Continued) predictive testing, 682 see also specific polymorphisms Cytokines corticosteroid adverse reactions, 514, 515b photodynamic therapy effects, 282 psoriasis, 288, 302–303 see also specific cytokines Cytolysis, complement-mediated, 332 Cytopenia, drug-induced, 690 Cytopenia, rituximab, 336 Cytostatic shampoos, 577t Cytostolic drug receptors, 4–6 Cytotoxic agents, 209–221, 210t adverse reactions, hematologic toxicity, 690 alkylating agents, 214–221 chlorambucil, 218–220 cyclophosphamide, 214–218 melphalan, 220–221 antimetabolites, 211–214 hydroxyurea, 213–214 thioguanine, 211–212 induced alopecia, 628 patient education, 211 subcategories, 210–211 see also specific drugs. Cytotoxic T-cells, extracorporeal, photochemotherapy effects, 273

D Dacarbazine, 407t, 414 adverse reactions, 410t indications, 408t Daily Med, 64 Dairy products, tetracycline interactions, 84 Dalbavancin, 78 Danazol, 446t, 447 pharmacology, 448t see also Attenuated androgens. Dandruff, abrasive treatment, 579 Dapsone, 222–233, 223t, 400 absorption, 223–224 acne vulgaris, 473t adverse effects, 228–229, 228b, 478 idiosyncratic, 229–231 adverse reactions agranulocytosis, 16, 695 hemolytic anemia, 695 hepatotoxicity, 686t hypersensitivity. see Dapsone hypersensitivity syndrome bioavailability, 223–224 contraindications, 228, 228b dermatologic uses, 478 drug interactions, 231, 232t excretion, 224–225 indications, 226–227, 226b linear IgA bullous dermatosis, 401 recurrent aphthous stomatitis, 670 mechanism for action, 225–226, 225t enzyme inhibition, 6t metabolism, 224

798

Index

Dapsone (Continued) microbiologic activity, 478 monitoring, 231–233, 233b pediatric dosing, 769t pharmacology, 223–226, 223t, 477–478 pregnancy and lactation, 231 pregnancy categories, 474t pregnancy/lactation risks, 718t, 724t rosacea, 473t Dapsone hypersensitivity syndrome, 15, 230–231 Dapsone-induced DRESS, timing of risk, 16 Darier’s disease, systemic retinoids, 251 Deafness, vancomycin, 79 Dechallenge hepatotoxicity diagnosis, 685 malignancy induction, 702, 702t Decubitus ulcers, 598 Deep chemical peels, 594–596 Deep venous thrombosis (DVT), rifamycins, 92 Defensins, psoriasis, 303 Degos’ disease (malignant atrophic papulosis), aspirin treatment, 363 7-Dehydrocholesterol (provitamin D3), 557–558 Dehydroepiandrosterone (DHEA), 367, 368f Delayed onset biofilms, dermal filler adverse reactions, 655 Delusional disorders, 391–394 Demeclocycline, 83–84 Dendritic cells extracorporeal photochemotherapy effects, 273b psoriasis, 287 Denileukin diftitox, 407t, 415–416 indications, 408t Dental calculus, 666 Dental plaque, 666 Dental trays, erosive gingivostomatitis treatment, 667 Deoxyribonucleic acid (DNA) synthesis, 159 Depression, 377, 380, 385–391 adherence, 36 finasteride adverse reactions, 377 systemic retinoid adverse reactions, 256 treatment, 386–388, 386t see also specific drugs. Dermal fillers, 653, 654b adverse reactions, 653–654 contraindications, 653b history, 653 indications, 653b types, 650–653 see also specific types Dermatitis atopic. see Atopic dermatitis azathioprine, 173 contact. see Contact dermatitis irritant contact. see Irritant contact dermatitis (ICD) perioral. see Perioral dermatitis

Dermatitis (Continued) seborrheic. see Seborrheic dermatitis stasis, 622 treatment, PUVA, 265 Dermatitis, systemic corticosteroids, 140–141 Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC), 64 Dermatologic diseases/disorders psychotropic agents, 395 treatment, bacitracin, 466–468 see also specific diseases/disorders Dermatology Life Quality Index (DLQI), 293–294 Dermatomyositis, 399–400 Dermatomyositis treatment, intravenous immunoglobulin, 399–400 Dermatomyosititis, rituximab, 331b, 335 Dermatophyte infections, salicylic acid treatment, 609 Dermatophytes, antifungal agent studies, 488–489, 489t Dermatoses immunobullous. see Immunobullous dermatoses immunologic, 265 inflammatory. see Inflammatory dermatoses treatment neoplastic, 265 photosensitivity. see Photosensitivity dermatoses pruritic, 265b treatment intravenous immunoglobulin, 402–403 narrowband UVB phototherapy treatment, 265 potassium iodide, 457 retinoids, 539 Dermis corticosteroid adverse reactions, 515–516, 515b α-hydroxy acids, 586–587 Desloratadine, 352t, 354 Desmolytic effects, salicylic acid, 608 Desogestrel, 374t indications, 380 Desquamation, α-hydroxy acids effects, 586 Detoxification definition, 3t hepatic drug metabolism, 678t, 679 metabolism, 7–8 Detoxification defects, hepatotoxicity, 679 Dexamethasone adverse reactions, 517 mouth rinses, 667 DEXA scans, bisphosphonate monitoring, 431 DHA. see Dihydroxyacetone (DHA) DHEA (dehydroepiandrosterone), 367, 368f DHS. see Drug hypersensitivity syndrome (DHS) Diabetes mellitus, hepatotoxicity risk factors, 681–682

Diabetic drug interactions, fluoroquinolones, 83t 4-4’-Diaminodiphenyl sulfone. see Dapsone Diarrhea, with β-lactam–β-lactamase inhibitors, 75 Dibucaine, 633t, 644, 645t Dicarboxylic acids, 477 Diclofenac adverse reactions agranulocytosis, 691t aplastic anemia (pancytopenia), 692t thrombocytopenia, 692t malignancy prophylaxis, 455 pregnancy/lactation risks, 720t Dicloxacillin, 74t–75t pregnancy/lactation risks, 717t Dienogest, 374t indications, 373 Diethylstilbestrol, public health crises, 55 Diffuse idiopathic skeletal hyperostosis (DISH), 256 Diffusion coefficient, percutaneous absorption, 8–9 Dihydrofolate reductase, 6t Dihydropteroate synthetase, 6t Dihydropyrimidine dehydrogenase deficiency, 26–27 drug metabolism, 26–27 genetic variants, 26–27 Dihydroxyacetone (DHA), 574–575 1,4-Dihydroxybenzene. see Hydroquinone 1,25-Dihydroxyvitamin D3, 560f Diiodohydroquinolone. see Iodoquinol Diltiazem bioavailability, 359 drug interactions, 738 grapefruit juice, 738–739 Raynaud’s phenomenon, 359 Dilution phenomenon, 764 Dioxybenzone, sunscreens, 567t Diphenhydramine pediatric dosing, 769t pregnancy/lactation risks, 720t Diphenhydramine hydrochloride, 349, 352t, 633t as injectable anesthetics, 633t mechanism of action, 635t pharmacology, 635t Dipyridamole, 363–364, 363b Dipyrone, agranulocytosis, 691t Discoid lupus erythematosus, corticosteroid treatment, 517 Discontinuation symptoms, venlafaxine adverse reactions, 387 Discontinuous symptoms doxepin adverse reactions, 387 selective serotonin reuptake inhibitors adverse reactions, 388 Discussion, informed consent, 755b, 756 Disease-specific database, malignancy induction, 702 DISH (diffuse idiopathic skeletal hyperostosis), 256

Index

Dissecting cellulitis of the scalp, systemic retinoid treatment, 251 Distribution drug interactions, 728 pharmacokinetics, 2–4, 2t protein-bound drugs, 728 systemic retinoids, 248 DNA-microarray studies polymorphism testing, 31 thiopurine methyltransferase testing, 28 DNA polymerase, drug inhibition, 6t DNA synthesis, PUVA effects, 264 Docetaxel, 407t, 415 adverse reactions, 410t indications, 408t Documentation informed consent, 755–756 patient monitoring, 765 DODAC (Dermatologic and Ophthalmic Drugs Advisory Committee), 64 Dose-limiting toxicity (DLT), 422 Dosing drug withdrawals, 66 pediatric patients, 769t see also specific drugs. Down regulation, 5t Doxepin, 352t, 355–356, 386–387, 386t, 395, 633t, 645t adverse reactions, 386–387 dermatologic conditions, 395 dosage, 386 mucositis (stomatitis), 672 pediatric dosing, 769t pregnancy/lactation risks, 720t Doxorubicin, 407t, 415 adverse reactions, 410t indictions, 408t Doxycycline, 83–84, 90t drug interactions PUVA, 265–266 systemic retinoids, 258t indications acne vulgaris, 85 lymphogranuloma venereum, 87 papulopustular rosacea, 85 plague, 87 pregnancy/lactation risks, 717t tularemia, 87 see also Tetracyclines. Doxycycline MR, 90t Drosperinone (DRSP), 373, 374t1, 375 indications, 380 DRSP. see Drosperinone (DRSP) Drug approval process, 49–53 general testing, 50, 50t generic drugs, 52 off-label drug use, 51–52 pharmacovigilance, 51 phase III testing, 51 see also Randomized controlled trials (RCTs). phase II testing, 51

Drug approval process (Continued) phase I testing, 51 phase IV testing, 51 special categories, 52 systemic drug bioequivalence, 52 see also Food and Drug Administration (FDA). Drug cessation drug safety, 19 hematologic toxicity treatment, 698 Drug efflux, tetracyclineresistance, 84 Drug errors, safety issues, 16 Drug hypersensitivity syndrome (DHS) hepatotoxicity, 678 tetracycline, 88 tetracycline effects, 88 see also specific drugs. drug-induced alkylating agents, 705–706 Drug-induced hyperlipidemia, 435–439 Drug interactions, 725–742 absorption, 726–727, 727f administration order effects, 735–736 consequences of, 726 cytochrome P-450. see Cytochrome P-450 (CYP); specific drugs definition, 725 distribution, 728 by drug category, 736–740, 737t drug complexes, 727 enterohepatic recirculation, 727 enzyme induction, 726 enzyme inhibition, 726 excretion, 730 gastric pH changes, 727 gastrointestinal motility, 727 genetic polymorphisms, 741 inducers added to substrates, 736 inhibitor added to substrate, 736 metabolism, 729–730 pharmacodynamics, 741 polymorphisms, 726 QTc intervals, 736, 737b risk assessment, 726 risk factors, 726, 727b substrate added to inducer, 736 substrate drug inhibition, 731t substrates added to inhibitors, 736 therapeutic index, 726 see also specific drugs. Drug metabolism aminolevulinic acid, 281, 281f azathioprine. see Azathioprine drug interactions, 15, 729–730 enzymes, 730 eutectic lidocaine and prilocaine, 641–642 liver. see Hepatic drug metabolism metabolic products, outcomes of, 730 methyl aminolevulinate, 281 pharmacokinetics, 2t, 7–8 phase I, 22–27

799

Drug metabolism (Continued) cytochrome P-450. see Cytochrome P-450 (CYP) dihydropyrimidine dehydrogenase, 26–27 drug interactions, 729–730 phase II, 22, 27–31 drug interactions, 729–730 folate pathway, 30–31 glucose-6-phosphate dehydrogenase, 29–30 glutathione S-transferase, 30 N-acetyltransferase, 29 P-glycoprotein, 22 polymorphisms, 27t thiopurine methyltransferase, 28–29 thymidylate synthase, 30–31 psoralens, 265, 265b systemic retinoids, 248 Drug partition coefficient, percutaneous absorption, 9 Drug Price Competition and Patient Restoration Act (1984), 52 Drug Quality and Security Act (DQSA), 760 Drug rash with eosinophilia and systemic symptoms (DRESS). see Drug Drug receptors agonists, 4–6 pharmacodynamics, 4–6 specificity, 4–6 Drug rechallenge hematologic toxicity treatment, 698 hepatotoxicity diagnosis, 685 malignancy induction, 702, 702t Drug safety, 12–20, 57f accidental effects, 13 anticipation, 13–16 baseline laboratory tests, 14–15 patient education, 14 patient selection, 13–14 definitions, 57 diagnosis, 12, 16–18 high-risk scenarios, 17–18 monitoring, 17 record keeping, 18 teamwork approach, 17 tests, 17 drug interactions, 15 see also Drug interactions; specific drugs. information, 16 management, 12, 19 patient role, 13 prevention, 12, 16 medication errors, 16 patient measures, 16 therapeutic interventions, 16 timing of risk, 16 risk factors, 15–16 spontaneous report programs, 58 standards of care, 13 see also Adverse drug reactions (ADRs).

800

Index

Drug Safety Communications, 63 drug withdrawal, 64 Drugs and Lactation Database (LactMed), 712t Drugs@FDA, 64 Drugs in Pregnancy and lactation: a reference guide to fetal and neonatal risk (Briggs), 711 Drug treatment history, compounding, 760–761 Drug weights, adherence measures, 34–35 Drug withdrawals, 64–66 cardiac arrhythmias, 65t cardiovascular adverse reactions, 65t cytochrome P-450, 66 dosing regimen, 66 liver toxicity, 64t medical principles, 66 by pharmaceutical company, 64 progressive multifocal leukoencephalopathy, 65t QT interval prolongation, 66 reasons for, 64 superceding actions, 64–65 toxicity, 66 transaminase elevations, 66 Dry mouth. see Xerostomia (dry mouth) Dry skin, 411t–412t Dupilumab, 402 pregnancy/lactation risks, 721t Dutasteride, 378–379 drug interactions, 379 indications, 378, 378b mechanism of action, 367 pharmacology, 378 DVT (deep venous thrombosis), rifamycins, 92 Dyclonine, 633t, 643, 645t Dysgeusia, 673t Dysphagia, 673t Dysplastic nevi, retinoid treatment, 538 Dysport, 658 Dystonin, 400

E EBA. see Epidermolysis bullosa acquisita (EBA) treatment EBV. see Epstein–Barr virus (EBV) Ecamsule (tetraphthalydine dicamphor sulfonic acid), sunscreens, 567t, 570t Ecological studies, 59t Econazole, 482t adverse effects, 484 indications, 484 pharmacology, 484 pregnancy/lactation risks, 719t ECP. see Extracorporeal photochemotherapy (ECP) Eczema, systemic retinoids, 252 Eczematous dermatoses, 583

Efalizumab adverse reactions malignancy induction, 701t, 706 withdrawal, 65t Efinaconazole, 482t, 485–486 pregnancy/lactation risks, 719t Efudex, label warning, 31 EGFR. see Epidermal growth factor receptor (EGFR) Electric medical records (EMR), drug safety, 18 Electronic mortar and pestle (EMP), 765 Electrophilic intermediates, hepatotoxicity mechanisms, 680–681 Elimination aminolevulinic acid, 281, 281f methyl aminolevulinate, 281 Emergency treatment, informed consent, 756 EMLA. see Eutectic lidocaine and prilocaine (EMLA) Emollients, corticosteroid vehicle, 514 EMR (electric medical records), drug safety, 18 Emulsifying agents corticosteroid vehicle, 514 sunscreens, 571 Emulsions corticosteroid vehicle, 514 sunscreens, 571 Endocrine system, thalidomide adverse reactions, 460–461 ENHANCE, ezetimibe, 443 Enolic acids, 454t Ensulizole (phenylbenzimidazole sulfonic acid), sunscreens, 567, 567t Enterohepatic recirculation definition, 3t drug interactions, 727 Enzyme induction, drug interactions, 726 Enzyme inhibition drug interactions, 726 pharmacodynamics, 6, 6t Eosinophilic granulomatosis with polyangiitis (EGPA), 399 Epidermal growth factor receptor (EGFR) expression, 406 papulopustular eruption, 406, 413f Epidermal growth factor receptor inhibitors (EGFRIs), 406–409, 407t adverse reactions, 409t hair alterations, 409 xerosis, 406–409 indications, 408t squamous cell carcinoma, 406 see also specific drugs. Epidermis corticosteroid adverse reactions, 515–516, 515b α-hydroxy acids effects, 586 Epidermolysis bullosa acquisita (EBA) treatment extracorporeal photochemotherapy, 278

Epidermolysis bullosa acquisita (EBA) treatment (Continued) intravenous immunoglobulin, 401 rituximab, 331b, 335 Epinephrine, 644–647 adverse reactions, 639 contraindications, 642b drug interactions, 647t indications, 642b, 644, 646b with injectable local anesthetic, 633t mechanism of action, 644 pharmacology, 644 therapeutic guidelines, 646–647 Epinephrine, pregnancy, 641 Epiphyseal closure, systemic retinoid adverse reactions, 257 Epoxide hydrolase polymorphisms, 680t Epstein–Barr virus (EBV), malignancy induction, 704 Erlotinib, 406, 407t adverse reactions, 409t indications, 406, 408t Erosive gingivostomatitis, 666–668 differential diagnosis, 666 mucocutaneous examination, 666 treatment, 666 anesthetics, 668 corticosteroids, 667 immunosuppressants, 667 intralesional corticosteroids, 668 mouth rinses, 667 systemic therapy, 668 Erosive oral lichen planus, extracorporeal, 277–278 Erosive pustular dermatoses, corticosteroid treatment, 518 Erythema, drug-induced, 595 photodynamic therapy, 285 Erythema nodosum leprosum, thalidomide treatment, 459 Erythema nodosum treatment aspirin, 363 nonsteroidal anti-inflammatory drugs, 454 Erythrocytes, thiopurine methyltransferase testing, 28 Erythromelalgia, nonsteroidal antiinflammatory drug treatment, 454 Erythromycin, 78 acne vulgaris, 473t, 476 adverse effects, 476 adverse reactions, 79 agranulocytosis, 691t hepatotoxicity, 681t pregnancy/lactation risks, 717t dosages, 81 formulations, 476t indications, 78–79 macrolide interactions, 740 microbiologic activity, 475–476 patch testing, 468t pharmacology, 475–476

Index

Erythromycin (Continued) pregnancy categories, 474t rosacea, 473t Escitalopram, 387, 388t Esophagitis, pill, 87 Estrogen-dependent malignancies, spironolactone, 372 Estrogens, teratogenicity, 713t Estrogen teratogenicity, spironolactone treatment, 372 Etanercept, 290–293, 290t adverse reactions, 292 malignancy induction, 701t biosimilars, 293 contraindications, 292 dosing schedules, 290 drug interactions, 293 indications, 290–293, 291b plaque psoriasis, 290–291 recurrent aphthous stomatitis, 671 long-term safety, 291 monitoring guidelines, 293 off-label use, 291–292, 292t pediatric patients, 291, 775 pharmacology, 290, 290t pregnancy/lactation risks, 723t therapeutic guidelines, 293 Ethanol use, hepatotoxicity, 681t, 685 Ethical perspective, informed consent, 754 Ethylhexyl triazone, sunscreens, 570t Etidocaine, pregnancy/lactation risks, 717t Etidronate, 431, 432t Etoposide, 407t, 414 adverse reactions, 410t indications, 408t Etretinate, 246 absorption/distribution, 248 market removal, 250 pharmacology, 247t Eutectic lidocaine and prilocaine (EMLA), 641–642, 642b, 645t absorption, 641 adverse reactions, 642 drug interactions, 643b excretion, 641 indications, 641–642, 642b metabolism, 641 off-label use, 642 pediatric patients, 643t pharmacology, 641 therapeutic guidelines, 642 Evaluation of treatments, 764–765 Evolence, 651 Examination, physician–patient relationship, 36 Exceptions, informed consent, 756, 756b Excimer laser, 269 Excipients, compounding, 762–764 Exclusion hepatotoxicity diagnosis, 685 malignancy induction, 702, 702t

Excretion drug interactions, 730 eutectic lidocaine and prilocaine, 641 pharmacokinetics, 2t, 8 psoralens, 264 systemic retinoids, 248 Exfoliative erythroderma, systemic corticosteroids, 141 Express consent, 754 EXPRESS II, infliximab, 293 EXPRESS I, infliximab, 293 Extended spectrum penicillins, 73 Extracellular matrix (ECM), 423–424 Extracorporeal photochemotherapy (ECP) adverse effects, 278, 279b combination therapy, 275–276 historical aspects, 271–272 immunotherapy, 271–272 indications, 274–279, 274b atopic dermatitis, 278 autoimmune dermatoses, 273–274 cutaneous T-cell lymphoma, 273, 274b–275b, 275 epidermolysis bullosa acquisita, 278 erosive oral lichen planus, 277–278 foliaceus, 278 graft-versus-host disease, 276–277 pemphigus vulgaris, 278 scleroderma, 277 T-cell-mediated autoimmune dermatoses, 273, 275b, 276–278 mechanism of action, 273, 273b monitoring, 275–278 treatment delivery, 272–273, 272f US Food and Drug Administrationapproved indications, 274–276, 274b Eye examination, drug safety, 14 Eyelids, contact dermatitis, 619 Ezetimibe, 443 clinical trials, 443

F FABP5 (fatty acid-binding protein 5), 532–533 Face, contact dermatitis, 619 Facial rhytides treatment botulinum toxin injection, 660–661 α-hydroxy acids, 587–588 Factitial wounds, 600 Famciclovir adverse effects, 122 drug interactions, 122 enzyme inhibition, 6t indications, 118b, 121 Herpes Zoster, 121–122 off-label uses, 122 pharmacology, 117t, 121 pregnancy/lactation risks, 721t risks, 118b Fas ligand/Fas receptor interactions, intravenous immunoglobulin therapy effects, 398

801

Fat tissue, distribution effects, 2–3 Fatty acid-binding protein 5 (FABP5), 532–533 Fatty liver, hepatotoxicity vs., 685 FDA. see Food and Drug Administration (FDA) Feasibility, compounding, 762–764 Feet, contact dermatitis, 621 Female(s) androgens, 367 systemic retinoid teratogenicity, 252–254 Female androgenetic alopecia, 378 Female-pattern alopecia drosperinone treatment, 368–369 minoxidil treatment, 628 Fenfluramine, withdrawal, 65t Fenofibrate, 439–443. see Fibric acid derivatives Ferric subsulfate, topical, 627 Fertility impairment, photodynamic therapy, 285 Fexofenadine, 354 dose, 354 pregnancy/lactation risks, 720t Fibrates, statin interactions, 441t Fibric acid derivatives, 439–443 absorption, 440 administration methods, 441 adverse reactions, 442 bioavailability, 440 contraindications, 441–442 drug interactions, 442–443 excretion, 440 indications, 441 mechanism of action, 440 metabolism, 440 monitoring, 443 pharmacology, 440 pregnancy, 441–442 structure, 442f therapeutic guidelines, 443 Fillers. see Dermal fillers Film formers, sunscreens, 571 Finasteride, 376–378 adverse reactions, 377–378 teratogenicity, 713t doses, 376 drug interactions, 378 indications, 376, 376b mechanism of action, 367 monitoring guidelines, 378 off-label uses, 376 pharmacology, 375b, 376 pregnancy/lactation risks, 724t First-generation antihistamines. see Antihistamines; specific drugs First-generation systemic retinoids, 247 First-pass effect definition, 3t P-glycoprotein, 729 FK506-binding protein (FKBP), 550 FKBP (FK506-binding protein), 550

802

Index

Fluconazole, 100, 100t adverse effects, 111 adverse reactions hepatotoxicity, 681t contraindications, 108–109 CYP effects, 732 deep fungal infections, 108 drug interactions, 112t drug risks profile, 109b enzyme inhibition, 6t indications, 104–105 mechanism of action, 103 off-label uses, 108 onychomycosis, 108 pediatric dosing, 769t pharmacokinetics in hair, 103 in nails, 102 in skin, 102 pregnancy/lactation risks, 719t structures, 101f tinea capitis, 106 tinea corporis, 106 Fluid overload, intravenous immunoglobulin adverse reactions, 403 Fluocinolone acetonide, 577t potency, 513t shampoos, 583 structure, 513f Fluorescent spot test, glucose-6-phosphate dehydrogenase polymorphism testing, 29–30 Fluoroquinolones, 71t–72t, 81–82 adverse reactions, 81–82 pregnancy/lactation risks, 717t antimicrobial activity, 81 dosage, 82 drug interactions, 82, 83t, 737t indications, 81 pharmacokinetics, 81 pharmacology, 81 5-Fluorouracil (5-FU), 495t, 502 adverse reactions, teratogenicity, 713t indications, actinic keratoses, 285–286, 537 metabolism, dihydropyrimidine dehydrogenase, 26 pregnancy/lactation risks, 720t Fluoxetine, 387, 387t–389t Flushing, β-blockers treatment, 362 Flutamide, 375 receptor interactions, 5t Fluvastatin, 436 dose, 440t drug interactions, 441t, 739 pharmacology, 440t structure, 437f–438f Fluvoxamine, 389t Folate pathway, phase II drug metabolism, 30–31 Folate (folic acid), synthesis inhibitors, 93–95 Foliaceus, extracorporeal photochemotherapy, 278 Folic acid effects, methotrexate, 159–160

Follicular epithelial hyperproliferation, acne vulgaris development, 536–537 Food and Drug Administration (FDA) advisory panels, 51 definition, 49–50 economics, 49–50 functions, 49–50 organization, 49–50 pregnancy categories, 711 safety information, 64 Food and Drug Administration Modernization Act (1998), 52 Food Drug and Cosmetic Act (1938), 50 public health crises, 55 Foods, 90t, 737t Forehead, botulinum toxin injections, 660 Formula instructions, compounding, 764 Formulations bioavailability, 4 percutaneous absorption, 10–11 psoralens, 264b Foscarnet, 495t, 497 Fractures, atypical, bisphosphonate adverse reactions, 434 Frontal fibrosing alopecia, 378 Frontal scalp, 376 Fruit acids. see α-hydroxy acids (AHA) Full disclosure, informed consent, 755 Fumaric acid esters (FAEs), 452 Fungal infections tumor necrosis factor inhibitor adverse reactions, 299 see also Antifungal agents, systemic; Antifungal agents, topical; specific infections

G GA. see Glycolic acid (GA) Gabapentin, 462–463 adverse reactions, 463 contraindications, 463b off-label uses, 463 pharmacology, 448t Gabapentin, burning mouth syndrome, 675 Galactose, 586 Garlic, drug interactions, 739t Gastric pH absorption effects, 2 drug interactions, 727 Gastric ulcers, bisphosphonate adverse reactions, 433 Gastrointestinal disorders, 425t Gastrointestinal effects, dapsone, 230 Gastrointestinal system absorption, 22, 22t adverse reactions, systemic retinoids, 253b–254b colchicine, 451 drug interactions, 727 excretion, pharmacokinetics, 8 G-CSF (granulocyte colony-stimulating

factor), drug-induced agranulocytosis management, 698 Gefitinib, 406, 408t Gels as base, 762 classification, 763t erosive gingivostomatitis treatment, 666 percutaneous absorption, 10t sunscreens, 571 Gemcitabine, 407t, 416 adverse reactions, 410t indications, 408t Gemfibrozil, 439–443. see Fibric acid derivatives Gene duplication, CYP2D6, 26 Generalized pustular psoriasis (GPP), systemic retinoids, 250 Generic drugs, legislation, 52 Genetics hepatotoxicity risk factors, 681–682 polymorphisms. see Polymorphisms Genistein, 625t Genital herpes simplex virus infections, acyclovir treatment, 494 Genital warts. see Condylomata acuminata (genital warts) treatment Gentamicin, 471 bacterial coverage, 467t mechanism of action, 467t patch testing, 468t pregnancy categories, 468t for wound care and minor topical antibacterial infections, 467t Gentian violet, oral candidiasis treatment, 668 Γ-glutamyl transpeptidase, 687t Ginger, drug interactions, 739t Gingival hyperplasia, 673t Gingivitis, 666 Gingivostomatitis acute necrotizing ulcerative, 671 erosive. see Erosive gingivostomatitis Gingivostomatitis, herpetic, 668 Gingko (Gingko biloba), drug interactions, 739t Ginseng, drug interactions, 739t Glabella, botulinum toxin injections, 664 Glogau scale, photoaging, 594, 594t Glossodynia, 673t Glucocorticoid(s) see also Corticosteroid(s) Glucocorticoid effects, systemic corticosteroids, 137, 138t Glucocorticoid receptors, expression, 514, 515b Gluconolactone, 586, 586f, 588 Glucose-6-phosphate dehydrogenase (G6PD) deficiency, dapsone adverse reactions, 695 drug safety, 15 drugs of importance, 29 phase II drug metabolism, 29–30

Index

Glucose-6-phosphate dehydrogenase (G6PD) (Continued) polymorphisms, 27t, 29 epidemiology, 30t testing, 29–30 Glutathione depletion, pharmacogenetics, 8 Glutathione S-transferase (GST) defects, 680t phase II drug metabolism, 30 polymorphisms, 27t, 680t Glycerin, 762t Glycolic acid (GA), 586–587, 592 administration, 585 indications hyperpigmentation, 588 photoaging, 587–588 rosacea, 588 photosensitivity, 590 Glycopyrrolate, 446–447, 446t, 448t see also Anticholinergic drugs. Gold adverse reactions aplastic anemia, 692t hematologic toxicity, 697 thrombocytopenia, 697 eyelid contact dermatitis, 619 Gonadotropin-releasing hormone analogs, 381 Gorlin syndrome, 423 G6PD. see Glucose-6-phosphate dehydrogenase (G6PD) GPP (generalized pustular psoriasis), systemic retinoids, 250 Graft-versus-host disease (GVHD), 423 treatment extracorporeal photochemotherapy, 276–277 intravenous immunoglobulin, 402 pimecrolimus, 555 PUVA, 269b rituximab, 331b, 335 thalidomide, 459 Gram-negative organisms clindamycin, 95 fluoroquinolones, 81 rifampin, 87 tetracyclines, 84 Gram-positive organisms, macrolides, 78 Granulocyte colony-stimulating factor (G-CSF), drug-induced agranulocytosis management, 698 Granuloma annulare, corticosteroid treatment, 517 Granuloma faciale, tacrolimus treatment, 552 Granulomatosis with polyangiitis (GPA), 399 Granulomatosis with polyangiitis and microscopic polyangiitis, rituximab therapy, 334 Granulomatous dermatoses, antimalarial agents, 238

Granulomatous dermatoses treatment adalimumab, 296 etanercept, 291 infliximab, 294 tetracyclines, 86 Granulomatous hepatotoxicity, 685t Grapefruit juice interactions, 738–739 Green tea (Camellia sinensis), 381 polyphenols, 625t Grepafloxacin, withdrawal, 65t Griseofulvin, 100, 100t adverse reactions contraceptive failure, 712t pregnancy/lactation risks, 713t dosages pediatric dosing, 769t indications, 104–105 off-label uses, 108 pityriasis (tinea) versicolor, 106 pregnancy/lactation risks, 719t tinea capitis, 106 tinea corporis, 106 Growth effects, corticosteroids, 519 GST. see Glutathione S-transferase (GST) Guselkumab adverse effects, 324 efficacy, 322–324 pharmacokinetics, 322 pharmacology, 322 phase III clinical trials, 323t, 324 pregnancy/lactation risks, 723t

H HA. see Hyaluronic acid (HA) Habits, hepatotoxicity risk factors, 682t Hair epidermal growth factor receptor inhibitors adverse reactions, 409 scalp contact dermatitis, 618 systemic retinoid adverse reactions, 255b, 257 Hair growth, 426 Hairy tongue, 669–670 Half-lives definition, 3t metabolism, 8 systemic retinoids, 248 Hands, contact dermatitis, 621 H1 antihistamines, 80t Hartnup disease, niacinamide treatment, 453 HCQ. see Hydroxychloroquine (HCQ) HDAC (histone deacetylase) inhibitors, 415 Head lice treatment malathion, 507 nonpharmacological treatment, 509 Hearing loss, vancomycin, 78 Hedgehog (Hh) pathway adverse effects alopecia, 424–426 breastfeeding and menses, effects on, 424 cutaneous malignancy risk, 426 dose-limiting toxicities, 424–426

803

Hedgehog (Hh) pathway (Continued) hair growth, effects on, 426 muscle cramps, 424–426 muscle spasms, 424–426 pediatric and geriatric risk, 427 reversible depression, 424–426 taste disturbances, 426 teratogenicity, 424 treatment resistance, 426–427 clinical use, 421–423 US Food and Drug Aministrationapproved indications, 421–423 drug interactions, 427, 428t itraconazole therapy, 427 monitoring guidelines, 427 off-label dermatologic uses graft-versus-host disease (GVHD), 423 lymphoma, 423 melanoma, 424 neoadjuvant use before surgery, 423 neurofibromatosis, 424 nevoid basal cell carcinoma syndrome, 423 photoaging, 424 systemic sclerosis (SSc), 423–424 trichoepitheliomas, 424 pharmacology absorption, 420 distribution, 420 excretion, 421, 422f inhibitors, 420–421, 420t, 425t, 425b metabolism, 421, 422f structure, 420 posaconazole, 427 Hemangiomas, infantile, 362 Hematologic toxicity, 689–698 drugs, 693–697 antimalarials, 696 azathioprine, 693–694 chlorambucil, 694 colchicine, 696–697 cyclophosphamide, 694 dapsone, 695 fluoroquinolones, 82 gold, 697 hydroxyurea, 694 interferons, 695 methotrexate, 693 miscellaneous drugs, 697 mycophenolate mofetil, 697 penicillamine, 697 rituximab, 697 sulfonamides, 695–696 systemic retinoids, 253b, 257–258 trimethoprim–sulfamethoxazole (TMP-SMX), 94 tumor necrosis factor inhibitors, 300 idiosyncratic reactions, 690 intravenous immunoglobulin, 403 mechanisms, 690 risk prediction, 690–691 timing, 690

804

Index

Hematologic toxicity (Continued) treatment, 698 see also specific toxicities Hemolytic anemia, drug-induced, 690 dapsone, 695 Hemostasis, epinephrine, 644 Hepatic drug metabolism, 678–679 bioactivation, 679 biotransformation, 679 conjugation reactions, 679b detoxification, 679 polymorphisms, 678t, 679 see also Cytochrome P-450 (CYP). Hepatitis B monitoring, 337 reactivation, 336 tumor necrosis factor inhibitor adverse reactions, 299–300 Hepatitis, systemic retinoid adverse reactions, 257 Hepatocellular toxicity, 680–681, 684t Hepatotoxicity, 679 cholestasis, 678, 683, 684t classification systems, 683 detoxification defects drug hypersensitivity syndrome, 680 hepatocellular toxicity, 681t mechanisms, 680–681 steatosis progressing to fibrosis, 682b diagnosis, 685–686 diagnostic algorithm, 685 liver function tests, 686 referral criteria, 685 differential diagnosis, 685, 687t drugs, 684–685 fluoroquinolones, 82 infliximab, 294 ketoconazole, 15 niacinamide, 453 rifamycins, 92 systemic retinoids, 253b, 257 tetracycline, 89 drug withdrawals, 64t granulomatous, 685t hepatocellular toxicity, 684t hypersensitivity, 684t information dissemination, 682–683 ischemic, 685t management, 686–687 mechanisms cellular targets, 681t CYP inducers, 680 electrophilic intermediates, 680–681 molecular targets, 681t neoantigens, 680–681 reactive intermediates, 680 structural targets, 681t toxic vs. idiosyncratic mechanisms, 681 predictors, 683 reversibility, 682b risk factors, 681–682, 682t timing, 682, 682b

Herbal remedies, 381 drug interactions, 739, 739t Hereditary angioedema, attenuated androgen treatment, 447 Herpes gestationis treatment corticosteroids, 401 intravenous immunoglobulin, 401. see Pemphigoid gestationis (herpes gestationis) treatment Herpes labialis, penciclovir treatment, 496 Herpes simplex virus (HSV) infection treatment acyclovir, 494 cidofovir, 497 α-hydroxy acids, 590 imiquimod, 498 indications, 115–118 systemic therapy, 667 Herpes simplex virus labialis, acyclovir treatment, 494 Herpes simplex virus vaccines, 123 Herpes virus infections see also specific infections; specific viruses Herpes zoster treatment aspirin, 363 corticosteroids, systemic, 141 indications, 118 Herpetic gingivostomatitis, 668 Heteroarylacetic acids, 454t HHV-8 (human herpesvirus-8) infection, malignancy induction, 704 HHVs. see Human herpes viruses (HHVs) Hidradenitis suppurativa, adalimumab, 295–296 High-density lipoproteins (HDLs), 435 High-risk patients, drug safety, 13 High therapeutic index, second generation antihistamines, 352 Hirsutism treatment cimetidine, 375 drosperinone, 375 finasteride, 375 spironolactone, 371 Histamine mast cell production, 350 urticaria, 356–357 see also Antihistamines Histamine H1 receptors, 350 plasticity, 350 Histamine H2 receptors, 350, 355 T cells, 350 Histamine H4 receptors, knockout mice, 350 Histamine receptors, 350 see also specific receptors Histamine suppressor factor (HSF), 350 Histiocytosis X (Langerhans’ cell histiocytoses), PUVA treatment, 265b Histone deacetylase inhibitors, 407t indications, 408t Histone deacetylase (HDAC) inhibitors, 415

Histoplasmosis, tumor necrosis factor inhibitor, adverse reactions, 299 HIV infection drug treatment see also specific drugs. hepatotoxicity risk factors, 682t HMG-CoA reductase inhibitors. see Statins Homosalate, sunscreens, 567t Hormonal contraceptives drug interactions, 740 rifamycins, 93t tetracyclines, 90t failure, 712, 712t oral. see Oral contraceptives Hormone preparations, 379–381 Hospital-acquired methicillin-resistant Staphylococcus aureus, vancomycin treatment, 97 HSF (histamine suppressor factor), 350 Human antichimeric antibodies (HACA), rituximab, 336 Human herpesvirus-8 (HHV-8) infection, malignancy induction, 704 Human herpes virus (HHV) infections therapeutic guidelines, 122 treatment see also specific drugs vaccines, 122–123 see also specific infections Human immunodeficiency virus (HIV) infections, 123–124 combination medications, 124 integrase strand transfer inhibitors, 124 nucleoside/nucleotide reverse transcriptase inhibitors, 124 vaccine development, 124 Human papillomavirus infections, malignancy induction, 704 Humectants corticosteroid vehicle, 514 urea effects, 614 Hyaluronic acid (HA) as filler, 651, 652t with lidocaine, 651 Hydrocodone, pregnancy/lactation risks, 717t Hydrocortisone. see Cortisol (hydrocortisone) Hydrogels, 763t Hydrogen peroxide (HP), 500, 630 Hydroquinone with polyhydroxy acids, 588 pregnancy/lactation risks, 724t Hydroxychloroquine (HCQ), 402 pregnancy/lactation risks, 722t–723t Hydroxyurea, 213–214 adverse reactions, pregnancy/lactation risks, 713t hematologic toxicity, 694 Hydroxyzine pediatric dosing, 769t pregnancy/lactation risks, 720t Hygiene, oral, erosive gingivostomatitis treatment, 666

Index

Hygroscopic effects, urea, 614 Hylaform, 651 Hypercalcemia, vitamin D3 adverse reactions, 561 Hypercholesterolemia, systemic retinoid adverse reactions, 254b Hyperglycemia, testing, 15 Hyperhidrosis, treatment, 627 anticholinergic drugs, 446–447 botulinum toxin injections, 661 salicylic acid, 610 Hyper-IgE syndrome (Job’s syndrome), 309–310 Hyperkalemia, spironolactone treatment, 372 Hyperkeratosis treatment, 607–615 salicylic acid, 610 sulfur. see Sulfur urea. see Urea Hyperlipidemia, drug-induced, 435–439 cyclosporine, 436 retinoids, 435–436 statins. see Statins Hyperpigmentation, α-hydroxy acid treatment, 588 Hyperproliferation, follicular epithelial, acne vulgaris development, 536–537 Hypersensitivity abacavir, 31 aspirin, 363 bexarotene, 435 cephalosporins, 76–77 denileukin diftitox, 416 dermal filler adverse reactions, 653–654 epinephrine, 644 fluoroquinolones, 82 glycopeptides, 78 hepatotoxicity, 684t infliximab, 294 intravenous immunoglobulin, 403 penicillins, 73 photodynamic therapy, 285 tetracycline effects, 88 trimethoprim–sulfamethoxazole, 94 Hypersensitivity syndrome, dapsone, 14 Hypertension benign intracranial, tetracycline effects, 87–88 venlafaxine adverse reactions, 390 Hypertriglyceridemia fibric acid derivative treatment, 441 systemic retinoid adverse reactions, 254b Hypnosedative effects, thalidomide, 458 Hypoallergenic products, scalp contact dermatitis, 618–619 Hypoallergenic shampoos, 577t Hypoglycemia, salicylic acid adverse reactions, 611 Hypothalamic-pituitary-adrenal-axis function, systemic corticosteroids, 137 Hypothalamic-pituitary-adrenal-axis suppression, 148–151 adrenal crisis, 149–150 adrenal insufficiency, 148–151

Hypothalamic-pituitary-adrenal-axis suppression (Continued) corticosteroid withdrawal syndrome, 149–150 laboratory tests, 149 stress responsiveness, 149 Hypothalamus–pituitary axis (HPA) corticosteroid adverse reactions, 519 function tests, 520 suppression see also specific diseases/disorders Hypothyroidism, potassium iodide adverse reactions, 457

I Ibandronate, 431 metabolism, 431 monthly dosing, 433 IBD. see Inflammatory bowel disease (IBD) Ibuprofen, urticaria treatment, 455 ICD. see Irritant contact dermatitis (ICD) Ichthyosiform dermatoses, systemic retinoid treatment, 251 Ichthyosis treatment α-hydroxy acids, 587 salicylic acid, 609 Idiopathic intracranial hypertension. see Pseudotumor cerebri (PTC) (idiopathic intracranial hypertension) Idiosyncratic reactions, hematologic toxicity, 690 Idoxuridine, 497 IFN-α. see Interferon-α (IFN-α) IL-23. see Interleukin-23 (IL-23) Iloprost, 365 IL-17 (interleukin-17), psoriasis, 288 IL-22 (interleukin-22), psoriasis, 288f, 302–303, 304t Imatinib, 407t, 413 adverse reactions, 409t indications, 408t Imidazoles drug interactions, 737 see also specific drugs Imiquimod, 495t, 498 actinic keratoses treatment, 284t, 285–286 pregnancy/lactation risks, 720t structure, 496f IMMhance trial, 327 Immune cell trafficking, intravenous immunoglobulin therapy effects, 398 Immune hemolytic anemia, drug-induced, 697 Immune system clofazimine effects, 449 finasteride adverse reactions, 377 Immune thrombocytopenia, tetracycline effects, 89 Immunobullous dermatoses azathioprine, 172–173 methotrexate, 161–162 tetracyclines, 86

805

Immunokines, 407t, 417 indications, 408t Immunologic dermatoses, PUVA treatment, 265 Immunomodulation thalidomide, 458 Immunosuppressants/immunosuppression drug interactions PUVA adverse reactions, 264 indications erosive gingivostomatitis, 667 systemic lupus erythematosus, 402 see also specific drugs Immunosuppression carcinogenesis, 144 Immunosuppressive effects, methotrexate, 159 IMMvent trial, risankizumab, 327 Imuran. see Azathioprine Index to Drug Specific Information, 64 Indoles, 454t Indomethacin adverse reactions agranulocytosis, 691t aplastic anemia, 692t indications ultraviolet-induced erythema, 455 urticaria, 455 Infantile hemangiomas, β-blocker treatment, 362 Infants. see Pediatric patients Infections drug-induced chemical peels, 595–596 interleukin-12/23 inhibitors, 310 intravenous immunoglobulin, 402 rituximab, 336 tetracycline, 86 tumor necrosis factor inhibitors, 299 interleukin 17 inhibitors, 318 secondary, 88 treatment, macrolides, 78–79 see also specific infections Infertility, photodynamic therapy, 285 Infiltrative local anesthesia, 636–637 Inflammation acne vulgaris development, 536–537 percutaneous absorption, 9t Inflammatory bowel disease (IBD) malignancy induction, 705 systemic retinoid adverse reactions, 256 see also Crohn’s disease. Inflammatory bowel disease, interleukin 17 inhibitors, 319 Inflammatory dermatoses treatment clofazimine, 449–450 macrolides, 79 tetracyclines, 86 Inflammatory nodules, dermal filler adverse reactions, 654 Inflammatory phase, wound healing, 598 Infliximab, 293–296, 294b adverse effects, 294 adverse reactions, malignancy induction, 701t, 705t, 706

806

Index

Infliximab (Continued) biosimilars, 295 clinical trials, 293 contraindications, 294, 294b drug interactions, 294 indications, 293, 294b plaque psoriasis, 293 recurrent aphthous stomatitis, 671 monitoring guidelines, 294 off-label uses, 293–294 pediatric patients, 775–776 pharmacology, 289t, 293 pregnancy/lactation risks, 723t therapeutic guidelines, 294–295 Information dissemination, hepatotoxicity, 682–683 Informed consent, 753–758, 756 components, 755, 755b consent form, 755–756 discussion, 755b, 756 documentation, 755–756 drug safety, 14, 18 ethical perspective, 754 exceptions, 756, 756b full disclosure, 755 historical perspective, 754 legal principles, 754–755 litigation, 754 patient–physician interaction, 754 patient understanding, 756 prescriptions, 754 signed forms, 755–756 systemic drugs, 755–756 Infusion reactions definition, 410t extravasation, 411t–412t infliximab, 294 intravenous immunoglobulin, 403 rituximab, 335 Ingenol mebutate, pregnancy/lactation risks, 720t Ingredients, compounding, 762 Initiation step, carcinogenesis, 703 Injection site reactions adalimumab, 296 certolizumab pegol, 298 dermal fillers, 654 etanercept, 292 Inosine monophosphate dehydrogenase, drug inhibition, 6t Inotropic agents, 90t Inotropic agents interactions, fluoroquinolones, 83t Interferon(s) adverse reactions, hematologic toxicity, 695 see also specific types Interferon-α (IFN-α), 499 drug-induced thrombocytopenia, 692t Interleukin-23 (IL-23) psoriasis, 288 T-helper (Th17) pathway, 302–303

Interleukin(s) see also specific types Interleukin-12/23 inhibitors adverse effects, 310 clinical trials, 309 FDA approval, 305 immunologic properties, 303t infection and malignancy, 310 mechanisms of action, 303–305, 303f quality of life, 308–309 Interleukin 17 inhibitors, 313t adverse events, 318–319 brodalumab, 317–318 chronic proinflammatory diseases, 312 immunologic properties, 314t ixekizumab, 316–317 secukinumab, 313–316 Interleukin 23 inhibitors, 322t biologic agent development, 321 Food and Drug Administration approval, 322 guselkumab, 322–324 pharmacology, 322t for psoriasis, 328 risankizumab, 326–328 tildrakizumab, 324–326 Interleukin-12/23 pathway, 310 Interleukin-23 pathway (Th17 axis), 305, 311 Interleukin-17 (IL-17), psoriasis, 288 Interleukin-22 (IL-22), psoriasis, 288f, 302–303, 304t Intertriginous psoriasis treatment calcipotriene, 561 calcitriol, 562 Intralesional drugs. see specific drugs Intralesional immunotherapy, 499 Intrauterine devices, 374t, 379–380 Intravenous immunoglobulin (IVIg), 397–398 adverse reactions, 403 aspirin with, 399 contraindications, 399b derivation, 397–398 dosage, 404 future work, 404 historical aspects, 397 indications, 399b atopic dermatitis bullous pemphigoid, 400 chronic autoimmune urticaria, 402 cicatricial pemphigoid, 401 dermatomyositis, 399–400 dermatoses, 402–403 epidermolysis bullosa acquisita, 401 graft-versus-host disease, 402 Kawasaki’s disease, 398–399 linear IgA bullous dermatosis, 401 pemphigoid gestationis, 401 pemphigus foliaceus, 400 pemphigus vulgaris, 400 scleroderma, 400 systemic lupus erythematosus, 402 toxic epidermal necrolysis, 401–402

Intravenous immunoglobulin (IVIg) (Continued) mechanism of action, 398 monitoring guidelines, 403, 403b pharmacology, 398–404 pregnancy/lactation risks, 722t–723t structure, 398f therapeutic guidelines, 403–404 Inverse agonists, 5t Iodophors, antimicrobial shampoos, 577t Iodoquinol, 472 bacterial coverage, 467t mechanism of action, 467t pregnancy categories, 468t for wound care and minor topical antibacterial infections, 467t Ipilimumab, 407t, 417 adverse reactions, 409t indications, 408t iPLEDGE program, 254–255, 255b Iproniazid, withdrawal, 64t Irritancy α-hydroxy acids, 590 sunscreen adverse reactions, 572 Irritant contact dermatitis (ICD), 618 shampoo adverse reactions, 581 sunscreen adverse reactions, 572 Irritants, 617–622 tar, 614 vitamin D3, 563 Ischemia, epinephrine adverse reactions, 646 Ischemic hepatotoxicity, 685t Isoamyl methoxycinnamate, sunscreens, 570t Isoniazid, hepatotoxicity mechanisms, 679 Isotretinoin, 246t absorption/distribution, 248 adverse reactions teratogenicity, 713t historical perspective, 246 indications, 250 acne vulgaris, 250 metabolism, 248 monitoring, 259b pharmacology, 247t Isotretinoin pseudotumor cerebri, 14 Isoxazolyl penicillins, 73 Isradipine, 359 Itraconazole, 100, 100t adverse effects, 111 adverse reactions hepatotoxicity, 681t contraindications, 108–109 CYP effects, 737 deep fungal infections, 108 drug interactions, 112t, 727, 729 nifedipine, 737 drug risks profile, 109b enzyme inhibition, 6t indications, 104–105 mechanism of action, 103 off-label uses, 108 onychomycosis, 108

Index

Itraconazole (Continued) pharmacokinetics in hair, 103 in nails, 102 in skin, 102 pregnancy/lactation risks, 719t structures, 101f tinea capitis, 106 tinea corporis, 106 Ivermectin, 126–128, 131t adverse effects, 127–128 drug interactions, 128 formulations, 507t indications, 127 lactation, 128 mechanism of action, 127 pharmacology, 127 pregnancy/lactation risks, 718t, 721t resistance, 128 risks, 128b structure, 505f teratogenic effects, 128 therapeutic guidelines, 127 IVIg. see Intravenous immunoglobulin (IVIg) Ixekizumab dermatologic indications, 316 dosage, 316 efficacy outcomes, 316t off-label uses, 317 pharmacology, 316 plaque psoriasis, 316–317 pregnancy/lactation risks, 723t psoriatic arthritis, 317 safety and monitoring guidelines, 317

J Janus kinase inhibitors baricitinib, 207 mechanism of action, 203 monitoring, 206–207, 207b off-label uses, 203–204 adverse effects, 204–206 alopecia areata, 203 atopic dermatitis, 203 contraindications, 204–206 infections, 204–205 psoriasis, 203 vitiligo, 203–204 ruxolitinib, 207 therapy, 203 tofacitinib, 203–207 JC virus infection, rituximab adverse reactions, 336 Jessner’s solution, 593 Job’s syndrome (hyper-IgE syndrome), 309–310

K Kaposi’s sarcoma drug-induced, 708t treatment, alitretinoin, 536 viral infections, 704

Kawasaki’s disease, intravenous immunoglobulin, 398–399 Keloids, treatment calcium channel blockers, 360–361 retinoids, 539 Keratinization disorders, vitamin D3, 562 Keratinization, vitamin D3, 562 Keratinocystic odontogenic tumors (KOTs), 423 Keratinocytes á-hydroxy acids effects, 586 psoriasis, 287 Keratolytic agents, 608 salicylic acid, 608 sulfur, 611 urea, 614 see also specific drugs Keratolytic shampoos, 581 Keratoplastic agents, sulfur, 611 Ketoconazole, 100, 379, 482t absorption, 22t, 579 adverse effects, 484 adverse reactions, hepatotoxicity, 15, 681t, 686t anti-inflammatory properties, 490 antimicrobial shampoos, 577t CYP2C19 inhibition, 25 drug interactions, 727 indications, 484 pharmacology, 484 pregnancy/lactation risks, 719t shampoos, 579, 582 Ketotifen, 350 mechanism of action, 350 urticaria, 455 Kidney see under renal

L LABD. see Linear IgA bullous dermatosis (LABD) treatment Labeling, 62 benefits-risks, 63 lifestyle changes, 63 Laboratory tests baseline, 14–15 drug safety, 18 Lactate dehydrogenase (LDH), liver function tests, 687t Lactation risks, 711 acetaminophen, 716t acitretin, 723t acyclovir, 721t adalimumab, 723t albendazole, 509 aminolevulinic acid, 720t ammonium lactate, 724t amoxicillin, 716t–717t analgesics, 717t antibacterial agents, 715b, 717t antiscabetics and pediculicides, 721t apremilast, 723t azalides, 717t

807

Lactation risks (Continued) azathioprine, 722t–723t azithromycin, 717t brodalumab, 723t bupivacaine, 717t calcipotriene, 723t cefdinir, 717t cephalexin, 717t cephalosporins, 717t cetirizine, 720t chloroprocaine, 717t chlorpheniramine, 720t ciclopirox, 719t cidofavir, 721t ciprofloxacin, 717t clindamycin, 717t coal tar, 723t codeine, 717t corticosteroids, 520 crisaborole, 721t crotamiton, 721t cyclosporine, 722t–723t dapsone, 724t diclofenac, 720t dicloxacillin, 717t diphenhydramine, 720t doxepin, 720t doxycycline, 717t drugs, photodynamic therapy contraindications, 285 dupilumab, 721t econazole, 719t efinaconazole, 719t erythromycin, 717t etanercept, 723t etidocaine, 717t famciclovir, 721t fexofenadine, 720t finasteride, 724t fluoroquinolones, 82, 717t fluorouracil, 720t guselkumab, 723t H1 antihistamines, 355 hydrocodone, 717t hydroquinone, 724t hydroxychloroquine, 722t–723t hydroxyzine, 720t imiquimod, 720t infliximab, 723t information sources, 711, 712t ingenol mebutate, 720t intravenous immune globulin, 722t–723t ivermectin, 721t ixekizumab, 723t levofloxacin, 717t lidocaine, 717t lincosamides, 717t lindane, 721t local anesthetics, 717t loratadine, 720t luliconazole, 719t macrolides, 717t

808

Index

Lactation risks (Continued) malathion, 507, 721t mepivacaine, 717t methotrexate, 722t–723t metronidazole, 717t miconazole, 719t minocycline, 717t morphine, 717t mycophenolate mofetil, 722t–723t naftifine, 719t neomycin, 718t opioids, 716t oxiconazole, 719t oxycodone, 716t penicillin(s), 717t penicillin G, 717t penicillin V, 717t permethrin, 506, 721t pimecrolimus, 721t polymyxin B, 718t precipitated sulfur, 721t prilocaine, 717t procaine, 717t psoriasis therapies, 723t pyrethrins, 506 rifamycins, 92 rituximab, 336, 722t–723t salicylic acid, 718t secukinumab, 723t selenium sulfide, 724t silver sulfadiazine, 718t sodium sulfacetamide, 718t specific drugs, 714 spinosad, 508, 721t sulconazole, 719t sulfonamides, 717t systemic antiviral agents, 721t tacrolimus, 721t tavaborole, 719t tazarotene, 718t tetracaine, 717t tetracyclines, 89 tildrakizumab, 723t tioconazole, 719t tofacitinib, 722t–723t treatment, spironolactone, 373 tretinoin, 718t trimethoprim, 717t trimethoprim-sulfamethoxazole (TMP-SMX), 94–95 urea, 724t ustekinumaba, 723t valacyclovir, 721t see also Pregnancy risks Lactic acid, 585 hyperpigmentation treatment, 588 structure, 586f LactMed (Drugs and Lactation Database), 712t Lactobionic acid, 586 Lamisil. see Terbinafine Langerhans’ cell histiocytoses (histiocytosis X), PUVA treatment, 265b

Langerhans’ cells, corticosteroid adverse reactions, 514, 515b Lanosterol 14-α demethylase, drug inhibition, 6t Larva migrans treatment, antiparasitic agents, 509 Laser surgery, eutectic lidocaine and prilocaine, 642 Latent tuberculosis infection (LTBI), interleukin 17 inhibitors, 319 Lateral canthus, botulinum toxin injections, 664 LDH (lactate dehydrogenase), liver function tests, 687t LDLs (low-density lipoproteins), 435 Lecithin-retinol acyltransferase (LRAT), alltrans retinoic acid/retinol, 532 Legal principles, informed consent, 754–755 Legislation, 50, 50t biological agents, 52 Drug Price Competition and Patient Restoration Act (1984), 52 Food and Drug Administration Modernization Act (1998), 52 Food Drug and Cosmetic Act (1938), 50 general testing, 50, 50t generic drugs, 52 Kefauver-Harris drug amendments, 50 non-USA countries vs., 53 over-the-counter drugs, 52 Prescription Drug User Free Act (1992), 51 with products, 53 Leg ulcers chronic, contact dermatitis, 622 debridement, eutectic lidocaine and prilocaine, 642 Leiomyoma-associated pain, 361 Leishmaniasis cutaneous, rifamycins, 91 interleukin-12/23 inhibitors, 310 Leprosy treatment, clofazimine, 449 Leucoencephalopathy, progressive multifocal. see Progressive multifocal leukoencephalopathy (PML) Leukemia, drug-induced alkylating agents, 706 prevention/detection, 708t Leukocytes, extracorporeal photochemotherapy effects, 272–273 Leukopenia hematologic toxicity, 690 systemic retinoid adverse reactions, 257–258 Leukoplakia, oral, retinoids, 539 Leuprolide, 381 mechanism of action, 367 Levacetyl methadol, withdrawal, 65t Levigating agents, compounding, 762t Levocetirizine, 352t, 354 Levofloxacin, 82 pregnancy/lactation risks, 717t LHA (lipo-hydroxy acid), chemical peels, 593

Lichen planus oral, extracorporeal photochemotherapy treatment, 277–278 treatment corticosteroids, 517 pimecrolimus, 554 retinoids, 539 systemic retinoids, 252 tacrolimus, 551 Lichen sclerosus et atrophicus, corticosteroid treatment, 517 Lichen sclerosus treatment pimecrolimus, 555 tacrolimus, 552 Lichen simplex chronicus, 583 Licorice, drug interactions, 739t Lidocaine, 645t bioavailability, 632 excretion, 634 with hyaluronic acid, 651 injectable contraindications, 636b historical aspects, 632 indications, 636b intradermal, pregnancy/lactation risks, 717t mechanism of action, 635t pharmacology, 635t pregnancy, 641 structure, 634f viscous acute necrotizing ulcerative gingivostomatitis, 671 mucositis, 671 Lidocaine, topical, 632, 643 indications erosive gingivostomatitis, 668 recurrent aphthous stomatitis, 670 pregnancy/lactation risks, 717t Lifestyle changes, labeling, 63 Ligand-receptor binding, systemic retinoids, 249t Ligands, 5t Lime, sulfurated, 611, 611t Lincosamides, 95–96 pregnancy/lactation risks, 717t Lindane, 508 pregnancy/lactation risks, 721t structure, 505f Linear IgA bullous dermatosis (LABD) treatment dapsone, 401 intravenous immunoglobulin, 401 sulfapyridine, 401 vancomycin, 78 Linezolid, 96 Lipid(s), systemic retinoid adverse reactions, 255–256 Lipodermatosclerosis, attenuated androgen treatment, 447 Lipodystrophy, 148 Lipoglycopeptides, 78

Index

Lipo-hydroxy acid (LHA), chemical peels, 593 Lipophilic drugs absorption effects, 2 distribution effects, 2 excretion, 8 percutaneous absorption, 9t tetracyclines, 84 Lipoproteins, 435–436 5-Lipoxygenase inhibitors,fluoroquinolone interactions, 83t Lips, contact dermatitis, 619–620 Listerine, mouth rinses, 667 Litigation, informed consent, 754 Litton’s chemical peel, 594 Livedoid vasculopathy (atrophia blanche) treatment, 399 aspirin, 363 attenuated androgens, 447 pentoxifylline, 364 Liver drug metabolism. see Hepatic drug metabolism toxicity. see Hepatotoxicity. see under hepatic Liver biopsy, methotrexate, 166–167 Liver cirrhosis, terbinafine, 102 Liver failure, etanercept contraindications, 292 Liver function tests, 111–113 drug safety, 14 see also specific tests Liver transplantation, hepatotoxicity management, 687 Live vaccinations, interleukin 17 inhibitors, 319 Local anesthetics, 632 pregnancy/lactation risks, 717t topical, 633t see also specific drugs; specific types Local anesthetics, injectable, 632, 633t absorption, 632 adverse reactions, 637–640 allergic reactions, 639 injection procedure, 639–640 toxic effects, 637–639 bioavailability, 632 coinjectable vasoconstrictors, 644–647 drug interactions, 640 with epinephrine, 632 see also Epinephrine excretion, 634 historical aspects, 632 indications, 636b infiltrative, 636–637 mechanism of action, 634 metabolism, 632–634 off-label uses, 637 pharmacology, 632–634 pregnancy, 641 structure, 632, 634f therapeutic guidelines, 640–641 Local anesthetics, topical, 633t

Local ischemia, epinephrine adverse reactions, 646 Localized scleroderma, tacrolimus treatment, 552 Locally advanced BCC (LABCC), 421–423 Loratadine, 352t, 354 pregnancy/lactation risks, 720t Lotions, percutaneous absorption, 10t Lotrimin Ultra. see Butenafine Lovastatin, 436 dose, 440t drug interactions, 441t, 737 pharmacology, 440t structure, 437f–438f Low-density lipoproteins (LDLs), 435 LRAT (lecithin-retinol acyltransferase), alltrans retinoic acid/retinol, 532 Luliconazole, 482t, 485 pregnancy/lactation risks, 719t Lupus erythematosus, 237–238 cutaneous. see Cutaneous lupus erythematosus treatment treatment systemic retinoids, 252 tacrolimus, 552 thalidomide, 459 Lupus-like syndrome, tetracycline effects, 88 Lyme disease, tetracycline treatment, 73 Lymphocyte function-associated antigen 1 (LFA-1), 398 Lymphocytes, corticosteroid adverse reactions, 514, 515b Lymphogranuloma venereum, doxycycline treatment, 78 Lymphoma, 423 cutaneous T-cell. see Cutaneous T-cell lymphoma (CTCL) drug-induced, prevention/detection, 708t primary cutaneous B-cell. see Cutaneous B-cell lymphoma tumor necrosis factor inhibitor adverse reactions, 298–299

M MACE (major adverse cardiac events), ustekinumab, 303, 309–310 Macrolides, 78–81, 80t, 83t adverse reactions, 79 agranulocytosis, 691t pregnancy/lactation risks, 717t antimicrobial activity, 78 dosages, 81 drug interactions, 79–81, 80t, 737t, 740 statins, 441t systemic retinoids, 258t indications, 78–79 infants, 79 pharmacokinetics, 78 pharmacology, 78 pregnancy, 79 see also specific drugs

809

Macrophages corticosteroid adverse reactions, 136t psoriasis, 287 Maculopapular rash, 410t Maintenance therapy PUVA, 269 rituximab, 333–334 Major adverse cardiac events (MACE), ustekinumab, 303, 309–310 MAL. see Methyl aminolevulinate (MAL) Malathion, 507–508 formulations, 507t lactation, 507 pregnancy, 507 pregnancy/lactation risks, 721t Male(s) androgens, 367 systemic retinoid teratogenicity, 254 Male androgenetic alopecia, 378 Male-pattern androgenic alopecia, minoxidil treatment, 628 Malignancy induction, 700–701 assessment algorithm, 702t autoimmune diseases, 704–705 drug assessment, 701–703 assessment algorithm, 701–702, 702t case reports/series, 703 database comparison, 702 disease-specific database, 702 organ transplants, 703–704 SEER database, 702 voluntary reporting systems, 703 drugs involved, 701t azathioprine, 694 chlorambucil, 694 interleukin-12/23 inhibitors, 310 rituximab, 331 tacrolimus, 552–553 prevention, 707 risk-benefit assessment, 700–701 viral infections, 704, 704t see also Carcinogenesis Malignancy prevention, systemic retinoid treatment, 251–252 Malignancy prophylaxis, nonsteroidal anti-inflammatory drug treatment, 455 Malignant atrophic papulosis (Degos’ disease), aspirin treatment, 363 Malnutrition, hepatotoxicity risk factors, 682t Malpractice, 757–758, 757b Mandelic acid, 585–586 Mast cells corticosteroid adverse reactions, 514, 515b histamine reduction, 350 Mastocytosis, nonsteroidal anti-inflammatory drug treatment, 455 Maximum tolerated dose (MTD), 422 Medical decision making (MDM), 40 causation determination, 42–43, 42b evaluation, 43, 43b interpretation, 43–45, 43b longitudinal patient care decisions, 46–47, 46b

810

Index

Medical decision making (MDM) (Continued) patient care, 41 patient individualization and prioritization, 40–41, 40b prescriber responsibilities, 45–46, 45b realities, 47, 47b risk management, 45, 45b Medical history, chronic wound care, 598 Medication Electronic Monitoring System (MEMS), 35 Medicolegal risk management, 756–757, 757b Medium-depth chemical peels, 593–594 MedWatch Alerts, 64 MedWatch program, 57–58 Melaleuca alternifolia (Tea tree) oil, 508 Melanocyte stimulation, PUVA effects, 264 Melanoma, 424 drug-induced, prevention/detection, 708t induction imatinib, 413 organ transplantation, 707 PUVA, 15, 266, 707 Melasma, corticosteroid treatment, 519 Melphalan, 220–221 Memory aids, adherence effects, 38 MEMS (Medication Electronic Monitoring System), 35 Mentax. see Butenafine Menthyl anthranilate (meradimate), sunscreens, 567t, 568 Mepivacaine injectable, 633t pharmacology, 635t pregnancy/lactation risks, 717t structure, 634f therapeutic guidelines, 640 Mepyramine (Neoantergan), 349 Meradimate (menthyl anthranilate), sunscreens, 567t, 568 6-Mercaptopurine (6-MP), thiopurine methyltransferase, 28 Merkel cell carcinoma, viral infections, 704 Meta-analyses, 58–60 drug safety, 58 Metabolism. see Drug metabolism Metastatic BCCs (MBCCs), 421–423 Methemoglobinemia, eutectic lidocaine and prilocaine adverse reactions, 642 Methemoglobin reduction studies, glucose-6phosphate dehydrogenase polymorphism testing, 30 Methicillin-resistant Staphylococcus aureus (MRSA), 466–468 rifamycin treatment, 97 Methotrexate (MTX), 156–168, 400–401 absorption, 157 with acitretin, 250 adverse effects, 162–165 gastrointestinal effects, 165 hematologic, 163–165 hepatotoxicity, 162–163

Methotrexate (MTX) (Continued) malignancy induction, 165 pulmonary toxicity, 163 renal effects, 165 reproductive effects, 165 adverse reactions contraceptive failure, 711 cyclophosphamide, 694 cytopenia, 693 hematologic system, 693 hepatotoxicity, 17, 686t malignancy induction, 693, 701t, 706 pancytopenia, 16, 19 teratogenicity, 713t distribution, 157 drug interactions, 158t, 165, 740 sulfonamide, 741 enzyme inhibition, 6t excretion, 157–159 indications, 160, 160b mechanism of action, 159–160 medication errors, 16 metabolism, 157–159 methylene tetrahydrofolate reductase, 30 monitoring, 17, 165–167, 166b off-label uses, 161–162 pediatric patients, 773–774 adverse effects and monitoring, 773–774 dosage, 773 pharmacology, 157–160 pregnancy/lactation risks, 722t–723t risks, 160b structure, 157 therapeutic guidelines, 167–168 Methoxsalen, malignancy induction, 701t Methyl aminolevulinate (MAL) absorption, 280–281 bioavailability, 280–281 contraindications, 285 elimination, 281 formulation, 282 metabolism, 281 structure, 280, 281f Methylbenzylidene camphor, sunscreens, 570t Methylene-bis-benzotriazolyl tetra methylbutylphenol, sunscreens, 570t Methylene tetrahydrofolate reductase (MTHFR), 30 Metoprolol, 361–362 Metronidazole acne vulgaris, 473t, 477 adverse effects, 477 cutaneous ulcers, 477 microbiologic activity, 476 patch testing, 468t pharmacology, 476 pregnancy categories, 474t pregnancy/lactation risks, 717t rosacea, 473t, 476–477 seborrheic dermatitis, 477 Mevastatin, 436

MHP. see Monosymptomatic hypochondriacal psychosis (MHP) Miconazole, 482t adverse effects, 483 indications, 483 oral candidiasis, 669 pharmacology, 483 pregnancy/lactation risks, 719t Microvesicular steatosis, 685t Midazolam, antifungal interactions, 737 Milia treatment chemical peels, 595 Mineralocorticoid effects corticosteroids, systemic, 137 Mineral oils, 762t Mini-pill, oral contraceptives, 379 Minocycline, 83–84 adverse reactions hepatotoxicity, 686t pregnancy/lactation risks, 717t systemic retinoid interactions, 258t see also Tetracyclines Minocycline drug reaction, 15 Minocycline ER, 90t Minocycline IR, 90t Minoxidil, 618, 628 indications, 628 scalp contact dermatitis, 618 off-label use, 628 pregnancy, 628 structure, 627f Mirtazapine, 386t, 391, 392b MKIS. see Multitargeted kinase inhibitors (MKIS) Molecular size, percutaneous absorption, 9t Molecular targets, hepatotoxicity mechanisms, 681t Molluscum contagiosum treatment cantharidin, 502 cidofovir, 496 hydrogen peroxide, 500 imiquimod, 498 intralesional immunotherapy, 499 sinecathechin, 503 Monheit peel, 594 Monitoring drug safety, 17 methotrexate, 17 tumor necrosis factor inhibitors, 17 see also specific drugs Monobactams, 70 Monoclonal Antibodies, 416 Monoclonal antibody treatments, 302–305 see also specific drugs Monocytes corticosteroid adverse reactions, 514, 515b extracorporeal photochemotherapy effects, 273 Monosymptomatic hypochondriacal psychosis (MHP), 391–392, 392b

Index

Morphea, treatment tacrolimus, 552 vitamin D3, 562 Morphine, pregnancy/lactation risks, 716t Motivational interviewing techniques, adherence effects, 37–38 Mouth, dry. see Xerostomia (dry mouth) Mouth rinses, erosive gingivostomatitis treatment, 667 MRSA (methicillin-resistant Staphylococcus aureus), rifamycin treatment, 97 Mucocutaneous effects penicillamine adverse reactions, 456 systemic retinoid adverse reactions, 255 Mucocutaneous examination, erosive gingivostomatitis, 666 Mucosa, calcium channel blockers adverse reactions, 361 Mucosal pigmentation, 673t as adverse reactions, 673t oral. see Oral mucosa Mucositis (stomatitis), 671–672 definition, 410t grading, 672t Mucous membrane pemphigoid (MMP), 401 Mucous membrane pemphigoid, rituximab, 331b, 335 Mucous membrane pemphigoid treatment. see Cicatricial pemphigoid treatment Multiple sclerosis, malignancy induction, 705 Multistep model, carcinogenesis, 703 Multitargeted kinase inhibitors (MKIS), 407t, 409–413 adverse reactions, 413f indications, 408t see also specific drugs Mupirocin adverse effects, 470 bacterial coverage, 467t burns, 470 cutaneous bacterial infections, 470 mechanism of action, 467t microbiologic activity, 470 patch testing, 468t pharmacology, 469–470 pregnancy categories, 468t pregnancy/lactation risks, 718t resistance, 470 staphylococcal colonization, 470 for wound care and minor topical antibacterial infections, 467t Musculoskeletal and connective tissue disorders sonidegib adverse reactions, 425t vismodegib adverse reaction, 425t Musculoskeletal system, systemic retinoid adverse reactions, 253b Mutagenicity, photodynamic therapy, 285 Myalgia, systemic retinoid adverse reactions, 257 Mycobacterium infections treatment, clofazimine, 449 see also Tuberculosis

Mycophenolate(s), 178–185 autoimmune connective tissue disease, 181–185 adverse effects, 182 atopic dermatitis, 182 carcinogenicity, 182–183 contraindications, 182 dermatomyositis, 182 gastrointestinal toxicity, 183–184 lupus erythematosus, 181 systemic sclerosis, 182 vasculitis, 182 drug interactions, 183t, 185 hematologic, 184 immunobullous disease, 181 pemphigus, 181 infections, 184 mechanisms of action, 179 monitoring, 185, 186b off-label uses, 180–181 psoriasis, 180–181 pharmacology, 179, 179t pregnancy, 184–185 treatment, 185 Mycophenolate mofetil, 400–401 absorption, 22t adverse reactions hematologic toxicity, 697 malignancy induction, 701t drug interactions, 727 enzyme inhibition, 6t pregnancy/lactation risks, 722t–723t Mycophenolic acid. see Mycophenolate mofetil Mycosis fungoides treatment, systemic retinoids, 251 Mycostatin. see Nystatin Myeloperoxidase, drug inhibition, 6t MYHFR (methylene tetrahydrofolate reductase), 30 Myopathy fibric acid derivative adverse reactions, 442 finasteride adverse reactions, 377 Mytrex. see Nystatin

N Nadolol, flushing treatment, 362 Nafarelin, 381 Nafcillin, 74t–75t indications, 95 Naftifine, 482t, 486 anti-inflammatory properties, 490 enzyme inhibition, 6t pregnancy/lactation risks, 719t Naftin. see Naftifine Nail(s) á-hydroxy acid treatment, 589 systemic retinoid adverse reactions, 255b, 257 Nail avulsion treatment, urea, 615

Nail psoriasis treatment calcipotriene, 562 calcipotriene/topical betamethasone dipropionate, 562 calcitriol, 562 Naproxen, aplastic anemia, 692t Narcotics, drug interactions thalidomide, 461t see also specific drugs Narrowband UVB phototherapy, 267–268 adverse reactions, 268, 268t contraindications, 267, 268b treatment protocol, 267–268 protection, 268 Nasal adverse reactions, systemic retinoid adverse reactions, 255b Natalizumab, withdrawal, 65t Neck botulinum toxin injections, 664 contact dermatitis, 620 Necrobiosis lipoidica (diabeticorum) treatment aspirin, 363 pentoxifylline, 364 Necrotizing ulcerative gingivostomatitis, acute, 671 Neoantergan (mepyramine), 349 Neoantigens, hepatotoxicity mechanisms, 680–681, 681t Neomycin adverse effects, 469 bacterial coverage, 467t dermatologic uses, 469 mechanism of action, 467t microbiologic activity, 469 patch testing, 468t pharmacology, 468–469 pregnancy categories, 468t pregnancy/lactation risks, 718t for wound care and minor topical antibacterial infections, 467t Neoplasia, drug-induced, 692–693 see also Carcinogenesis Neoplastic dermatoses, narrowband UVB, phototherapy treatment, 265 Neoral. see Cyclosporine Nephrotoxicity cephalosporins, 77 neomycin, 469 Nerve fibers conduction, 634, 658f physiology, 657 subcategories, 634 Nervous system disorders sonidegib adverse reactions, 425t vismodegib adverse reaction, 425t Netherton’s syndrome pimecrolimus treatment, 555 tacrolimus systemic absorption, 553 Neural effects, thalidomide, 458–459 Neurofibromatosis, 424

811

812

Index

Neurologic adverse reactions doxepin, 387 intravenous immunoglobulin, 403 systemic retinoids, 253b tumor necrosis factor inhibitor, 300 see also specific diseases/disorders Neurologic examination drug monitoring, 17 thalidomide monitoring, 461 Neuromuscular system, botulinum toxin injections, 657 Neuropathic ulcers, 598 Neuropathy drug-induced. see Peripheral neuropathy; drug-induced peripheral. see Peripheral neuropathy; druginduced Neurotransmitters, nerve conduction, 657 Neutropenia as adverse reactions, 690 drug-induced, 698 interleukin 17 inhibitors, 319 Neutrophilic dermatoses, azathioprine, 173 Neutrophilic dermatoses treatment adalimumab, 296 colchicine, 450–451 etanercept, 291 infliximab, 294 thalidomide, 460 Neutrophil(s), psoriasis, 287 Nevirapine, adverse reactions HLA markers, 31t Nevoid basal cell carcinoma (NBCC) syndrome, 423 Niacinamide, 446t, 452–453 adverse reactions, 453, 454b doses, 453 off-label uses, 453 pharmacology, 452–453 Niacinamide-induced cutaneous changes, treatment, 454 Niacin-Induced Cutaneous Changes, treatment, 363 Nifedipine bioavailability, 359 indications Raynaud’s phenomenon, 359 wound healing, 360 itraconazole interactions, 737 Night vision, systemic retinoid adverse reactions, 257 Nile blue sulfate reduction, glucose-6phosphate dehydrogenase polymorphism testing, 30 Nilotinib, 407t, 413 adverse reactions, 409t Nimesulide, urticaria treatment, 455 Nitric oxide (NO) donors, 364 NMSC. see Non-melanoma skin cancer (NMSC) NNRTIs. see Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Nodules, inflammatory, dermal filler adverse reactions, 654 Non-aqueous bases, 762 Noncardioselective beta blockers, 772 Nongenital warts, trichloroacetic acid treatment, 501 Non-Hodgkin’s lymphoma, viral infections, 704 Noninflammatory nodules, dermal filler adverse reactions, 654 Non-melanoma skin cancer (NMSC) drug-induced PUVA, 266 prevention, systemic retinoids, 252 see also Basal cell carcinoma (BCC); Squamous cell carcinoma (SCC) Non-psychiatric disorders, psychotropic medications, 384 Nonsteroidal anti-inflammatory drugs (NSAIDs), 454–455, 454t adverse reactions, 455 contraceptive failure, 712 off-label uses, 454–455 pharmacology, 454 see also specific drugs Norgestimate, 374t indications, 380 North American Contact Dermatitis Group (NACDG), 468 NSAIDs. see Nonsteroidal anti-inflammatory drugs (NSAIDs) Nuclear receptors, tazarotene binding, 535 Nuremberg Code, informed consent, 754 Nutritional supplements, fluoroquinolone interactions, 83t Nutrition, hepatotoxicity risk factors, 682t Nystatin, 482t adverse effects, 481 indications, 481 oral candidiasis, 669 mechanism of action, 481 pharmacology, 481 pregnancy/lactation risks, 719t Nystop. see Nystatin

O Obesity distribution effects, 3 hepatotoxicity risk factors, 682t Obsessive-compulsive disorder (OCD), 394–395 definition, 394 symptoms and signs, 394b OCD. see Obsessive-compulsive disorder (OCD) Octinoxate, 568f Octinoxate, sunscreens, 567, 567t, 568f Octisalate, sunscreens, 567, 567t Octocrylene, sunscreens, 567, 567t Octyl methoxycinnamate, 568f sunscreens, 567, 567t Octyl salicylate, sunscreens, 567, 567t

Ocular adverse reactions corticosteroids, 520 systemic retinoids, 255b, 257 Ocular rosacea, tetracyclines, 86 Off-label dermatologic uses, hedgehog (Hh) pathway graft-versus-host disease (GVHD), 423 lymphoma, 423 melanoma, 424 neoadjuvant use before surgery, 423 neurofibromatosis, 424 nevoid basal cell carcinoma syndrome, 423 photoaging, 424 systemic sclerosis (SSc), 423–424 trichoepitheliomas, 424 Off-label uses, 51–52 adalimumab, 296 anthralin, 629 attenuated androgens, 447 becaplermin, 628 bleomycin, 499–500 capsaicin, 647 cidofovir, 496–497 clofazimine, 449–450 colchicine, 450–451 compounding, 761 etanercept, 291–292, 292t eutectic lidocaine and prilocaine, 642 finasteride, 376 5- fluorouracil, 502 gabapentin, 463 hydrogen peroxide, 500 imiquimod, 498 infliximab, 293–294 injectable local anesthetics, 637 intralesional immunotherapy, 499 minoxidil, 628 niacinamide, 453 nonsteroidal anti-inflammatory drugs (NSAIDs), 454–455 penicillamine, 456 pimecrolimus, 554–555 potassium hydroxide, 500 potassium iodide, 457 pregabalin, 463 PUVA, 265 retinoids, 251–252 sinecathechin, 503 spironolactone, 371 tacrolimus, 552 thalidomide, 459–460 trichloroacetic acid, 501 vitamin D3, 562–563 Oil in water emulsions, 763t Ointments erosive gingivostomatitis treatment, 666 percutaneous absorption, 10t Olanzapine, 393–394 Olanzapine, burning mouth syndrome, u2060 Oleaginous agents, 763t

Index

Omalizumab, 402 Onabotulinumtoxin A, 658 Oncogenes, 703 Onychomycosis children with, 108 fluconazole, 108 itraconazole, 108 terbinafine, 108 Opioids, pregnancy/lactation risks, 716t Opportunistic infections, 144 Oral candidiasis, 668–669 Oral contraceptives, 374t, 379–380 combination pill, 379 drug interactions, 379 mini-pill, 379 Oral hygiene, erosive gingivostomatitis treatment, 666 Oral leukoplakia, retinoids, 539 Oral lichen planus, erosive, 277–278 Oral mucosa, 665–666 terminology, 666 Organogels, 763t Organ transplantation, malignancy induction, 703–704, 707 melanoma, 707 squamous cell carcinoma, 707 Oritavancin, 78 Ornithine decarboxylase, 6t Osmotic nephrosis, 403 Osteonecrosis, 144 bisphosphonate adverse reactions, 434 prednisolone, 16 symptoms, 14 Osteoporosis, 144 corticosteroid adverse reactions. see Corticosteroid-induced osteoporosis systemic retinoid adverse reactions, 257 Ototoxicity, neomycin, 469 Outcome, drug safety, 60t Over-the-counter drugs, 674t legislation, 52 Oxaborole, in-vitro and in-vivo activity of, 483t Oxazolidinones, 96 Oxiconazole, 482t adverse effects, 484 indications, 484 pharmacology, 484 pregnancy/lactation risks, 719t Oxybenzone structure, 568f sunscreens, 567–568, 567t Oxybutynin, 446–447, 448t Oxycodone, pregnancy/lactation risks, 716t Oxymetazoline, 629–630 pregnancy/lactation risks, 718t Ozenoxacin adverse effects, 471 bacterial coverage, 467t dermatologic uses, 471 mechanism of action, 467t microbiologic activity, 471

Ozenoxacin (Continued) pharmacology, 471 pregnancy categories, 468t for wound care and minor topical antibacterial infections, 467t

P PABA (para-aminobenzoic acid), neck contact dermatitis, 620 Paclitaxel, 407t, 413f, 414–415 adverse reactions, 410t indications, 408t Padimate O structure, 568f sunscreens, 567t, 568f Pain management. see Analgesics salicylic acid treatment, 609–610 Palatability, erosive gingivostomatitis treatment, 666 Palmar-plantar erythrodysesthesia syndrome, 409–413, 411t–412t Palpable subcutaneous nodules, dermal filler adverse reactions, 654 Pamidronate, 431, 432t Pancreatitis, 143 Pancytopenia. see Aplastic anemia (pancytopenia) Panitumumab, 406, 407t adverse reactions, 409t indications, 406, 408t Panniculitis antimalarial agents, off-label uses, 239 potassium iodide treatment, 457 Papulopustular rash definition, 411t–412t epidermal growth factor receptor, 413f Papulopustular rosacea, doxycycline treatment, 85 Papulosquamous dermatoses, azathioprine, 173 Papulosquamous dermatosis treatment colchicine, 451 immunologic dermatoses, 265 pruritic dermatoses, 265b PUVA, 265 Para-aminobenzoic acid (PABA), neck contact dermatitis, 620 Paraneoplastic pemphigus, rituximab treatment, 331, 331b Parenteral, 3t Paronychia, 409t–410t Paroxetine, 385, 387t–388t PARP-1 (poly-(ADP-ribose) polymerase-1), 453 Partial agonists, 5t Patch-stage cutaneous T-cell lymphoma, corticosteroid treatment, 518 Patient(s) compounding triad, 760–761 drug safety, 13, 16 comprehension, 13–14

813

Patient(s) (Continued) education, 14 drug use instructions, 764 evaluation, adverse reactions, 22 informed consent physician interaction, 754 understanding, 756 monitoring, 764–765 documentation, 764–765 populations, adherence, 35 randomized controlled trials, 55–56 Sonidegib, laboratory abnormalities in, 428t Patient handouts, drug safety, 14 PCR (polymerase chain reaction), thiopurine methyltransferase testing, 28 PDE-5 inhibitors, 80t drug interactions, rifamycins, 93t PEARL, ustekinumab, 305 Pediatric patients adherence, 39 dosages, 769t etanercept, 291 eutectic lidocaine and prilocaine, 643t macrolides, 79 malignancies, tumor necrosis factor inhibitor adverse reactions, 299 photodynamic therapy contraindications, 285 psoriasis, calcipotriene treatment, 561 rituximab, 336 shampoo safety, 579 systemic therapy, 768 topical therapy, 768 see also specific patients Pediculoses treatment antiparasitic agents, 504 pyrethrins, 506 PEG 400, 762t PEGylated doxorubicin (PLD), 407t–408t, 415 adverse reactions, 410t Pellagra, niacinamide treatment, 453 Pemoline, withdrawal, 64t Pemphigoid gestationis (herpes gestationis) treatment corticosteroids, 401 intravenous immunoglobulin, 401 Pemphigus foliaceus treatment corticosteroids, 400 intravenous immunoglobulin, 400 rituximab, 331, 331b, 334 Pemphigus vulgaris, corticosteroids, systemic, 139–141 Pemphigus vulgaris treatment extracorporeal photochemotherapy, 278 intravenous immunoglobulin, 400 pentoxifylline, 364 rituximab, 331b, 333–334 Penciclovir, 495t, 496

814

Index

Penicillamine, 446t, 455–456 adverse reactions hematologic toxicity, 697 thrombocytopenia, 697 off-label uses, 456 pharmacology, 448t, 455–456 Penicillin(s), 70–73 adverse reactions, 73 agranulocytosis, 691t cross-reactions, 73 hypersensitivity, 73 pregnancy/lactation risks, 717t antimicrobial activity, 73 cephalosporin cross-reactivity, 73 dosages, 73 drug interactions, 73 extended spectrum, 73 indications, 73 acute necrotizing ulcerative gingivostomatitis, 671 penicillinase-resistant, 73 pharmacokinetics, 73 pharmacology, 70–73 second-generation, 73 third-generation, 73 see also specific penicillins Penicillinase-resistant penicillins, 73 Penicillin G, 70 pregnancy/lactation risks, 717t Penicillin V, 73 pregnancy/lactation risks, 717t Pentoxifylline, 364, 364b recurrent aphthous stomatitis, 670 Peptic ulcer perforation, 143 Percutaneous absorption, 8–11 formulations, 10–11 tachyphylaxis, 10 variables, 9t vehicles, 10 see also specific vehicles Pergolide, withdrawal, 65t Perianal warts, imiquimod treatment, 498 Periauricular thenar erythema with onycholysis (PATEO) syndrome, 415 Periodontitis, 666 Perioral dermatitis, 620 adverse reactions, 555 azelaic acid, 477 corticosteroid adverse reactions, 520 tetracyclines, 86 treatment pimecrolimus, 555 Peripheral neuropathy, 230 drug-induced, thalidomide, 460 Peripheral T-cell lymphoma (PTCL), 416 Permethrin, 504–506 adverse reactions, 506 formulations, 506t indications, 506 lactation, 506 mechanism of action, 506 pregnancy, 506

Permethrin (Continued) pregnancy/lactation risks, 721t structure, 505f Persistent erythema, 595 PGA score, 293–294 PGE2 (prostaglandin E2), 359 PGI2 (prostaglandin I2), 359 P-glycoprotein (PGP), 728–729 absorption, 22 drug metabolism, 22 first-pass effect, 729 inhibitors, 729, 730b polymorphisms, 27–28, 27t structure, 729f substrates, 729b PGP. see P-glycoprotein (PGP) PHA. see Polyhydroxy acids (PHA) pH, α-hydroxy acids formulations, 588 Pharmaceutical company, drug withdrawals, 64 Pharmacists, compounding triad, 761 Pharmacodynamics, 4–7 definition, 2, 2t, 4, 5t drug interactions, 741 antagonistic effect, 741 synergistic effects, 741 drug receptors, 4–6 enzyme inhibition, 6, 6t signal transduction, 6–7 transcription factors, 6–7 see also specific drugs Pharmacogenetics, 7 definition, 2t–3t Pharmacogenomics, 31–32 Pharmacokinetics, 1–2, 2t, 7–8 absorption, 2, 2t bioavailability, 2t concepts, 3t definition, 2, 2t distribution, 2–4, 2t excretion, 2t, 8 metabolism, 2t, 7–8 see also specific drugs Pharmacology, 1–11 hedgehog (Hh) pathway absorption, 420 distribution, 420 excretion, 421, 422f inhibitors, 420–421, 420t, 425t, 425b metabolism, 421, 422f structure, 420 intravenous immunoglobulin, 398–404 Pharmacovigilance, 54–61 definition, 54 drug approval process, 51 Pharmacy data, adherence measures, 35 Phase I drug metabolism. see Drug metabolism Phase II drug metabolism. see Drug metabolism Phase III testing, drug approval process, 51 Phase II testing, drug approval process, 51

Phase I testing, drug approval process, 51 Phase IV testing, drug approval process, 51 Phenylbenzimidazole sulfonic acid (ensulizole), sunscreens, 567 Phenylpropanolamine, withdrawal, 65t Phenytoin, hepatotoxicity, 681t PHN. see Postherpetic neuralgia (PHN) treatment PHOENIX 1 dosages, 308 interleukin-12/23 inhibitors, 309 ustekinumab, 309 PHOENIX 2 dosages, 308 interleukin-12/23 inhibitors, 309 ustekinumab, 309 Phosphodiesterase 4 apremilast, 201–202 adverse effects, 201–202 contraindications, 201–202 depression, 202 drug interactions, 202t gastrointestinal effects, 201 indications, 201, 201b off-label uses, 201 pharmacokinetics, 201 pharmacology, 201 suicide risk, 202 crisaborole, 202–203 adverse effects, 203 atopic dermatitis, 202 contraindications, 203 irritancy, 203 pharmacokinetics, 203 pharmacology, 203 inhibitor therapy, 200–203 mechanism of action, 200, 200f Phosphodiesterase-5 inhibitors, 364–365 Phospholipase A2, drug inhibition, 6t Phosphorus, bisphosphonate adverse reactions, 433–434 Photoaging, 424 Glogau scale, 594 treatment á-hydroxy acids, 587–588 chemical peels, 594 photodynamic therapy, 284–285 retinoids, 537–538 salicylic acid, 610 tretinoin, 529 vitamin C, 624–626 Photoallergic contact dermatitis, neck, 620 Photobiology, photodynamic therapy, 282 Photochemistry photodynamic therapy, 282 psoralens, 264 Photodermatoses antimalarial agents, off-label uses, 238 azathioprine, 173 Photodermatosis treatment, niacinamide, 453

Index

Photodynamic therapy (PDT) adverse reactions, 285 crusting, 285 erythema, 285 malignancy induction, 701t contraindications, 285 drug interactions, 285 indications, 283–284 actinic keratoses, 283–284 mechanism of action, 281–282 monitoring guidelines, 285 off-label uses, 284–285 precautions, 285 sunlight protection, 286 treatment regime, 282 see also Aminolevulinic acid (ALA); Methyl aminolevulinate (MAL) Photopheresis. see Extracorporeal photochemotherapy (ECP) Photoprotection, vitamin C, 624–626 Photosensitivity, 231 definition, 409t–412t dermatoses. see below fluoroquinolones, 82 α-hydroxy acids, 590 photodynamic therapy, 285–286 sunscreens, 572 tetracycline, 88 vitamin D3, 563 Photosensitivity dermatoses, treatment narrowband UVB phototherapy, 267 PUVA, 264 Photosensitizers, 90t Phototoxic reactions, photodynamic therapy, 285 Physician(s) compounding triad, 761 treatment adherence effects, 38 Physician-patient relationship adherence, 36, 36f, 36b examination, 36 Phytonadione (vitamin K), 627 Pigmentation disorders azelaic acid, 477 chemical peels, 595 α-hydroxy acids, 588 mucosa. see Mucosal pigmentation photodynamic therapy, 285 tetracycline, 88 treatment, retinoids, 538 Pill counts, adherence measures, 34–35 Pill esophagitis, tetracyclines, 87 Pilocarpine, xerostomia, 674 Pimecrolimus, 553 indications, 554 atopic dermatitis, 554 contact dermatitis, 555 cutaneous lupus erythematosus, 555 graft-versus-host disease, 555 lichen planus, 554 lichen sclerosus, 555

Pimecrolimus (Continued) Netherton’s syndrome, 555 perioral dermatitis, 555 psoriasis, 555 rosacea, 555 seborrheic dermatitis, 555 vitiligo, 554–555 lack of efficacy, 555 mechanism of action, 554 off-label use, 554–555 pharmacology, 554 pregnancy/lactation risks, 721t tacrolimus vs., 551 Pimozide, 392–393 dose, 392 drug interactions, 740 patient rapport, 392–393 Pitavastatin, 436 dose, 440t drug interactions, 441t pharmacology, 440t Pityriasis (tinea) amiantacea, 583 Pityriasis rubra pilaris, systemic retinoid treatment, 251 Pityriasis (tinea) versicolor, 106–108 griseofulvin, 106 prophylaxis, 108 terbinafine, 106 Pityrosporum folliculitis, 583 Plague, doxycycline treatment, 87 Plaque, dental, 666 Plaque psoriasis azelaic acid, 477 brodalumab, 317 chronic, anthralin, 629 definition, 305 ixekizumab, 316–317 retinoids, 538 secukinumab, 314–315 treatment, 308 calcipotriene, 560–561 etanercept, 290–291 PLD. see PEGylated doxorubicin (PLD) Pluronic-lecithin organogel (PLO), 763 PLX 4032. see Vemurafenib (PLX 4032/ RG7204/RO5185426) PML. see Progressive multifocal leukoencephalopathy (PML) P3NP, liver function tests, 687t Podofilox, 495t, 500–501 Podophyllin, 500–501 Polio vaccine (Cutter laboratories), public health crises, 55 Poly-(ADP-ribose) polymerase-1 (PARP-1), 453 Polyene antibiotics, in-vitro and in-vivo activity of, 483t Polyenes, 481, 482t see also specific drugs Polyhydroxy acids (PHA) absorption, 586 definition, 586

815

Polyhydroxy acids (PHA) (Continued) effects, 587 with hydroquinone, 588 with retinyl acetate, 589–590 structure, 586 see also specific acids Poly-L-lactic acid, as filler, 651–653 Polymerase chain reaction (PCR), thiopurine methyltransferase testing, 28 Polymethylmethacrylate, as filler, 653 Polymorphisms, 21–33 adverse reactions, 22, 31 cytochrome P-450. see Cytochrome P-450 (CYP) drug interactions, 741 tests for, 31 Polymorphonuclear leukocytes, corticosteroid adverse reactions, 514, 515b Polymyxin B adverse effects, 468 adverse reactions, pregnancy/lactation risks, 718t bacterial coverage, 467t dermatologic uses, 468 mechanism of action, 467t microbiologic activity, 468 patch testing, 468t pharmacology, 468 pregnancy categories, 468t pregnancy/lactation risks, 718t for wound care and minor topical antibacterial infections, 467t Population size, randomized controlled trials, 55 Population studies, drug-induced agranulocytosis, 690 Porphyria cutanea tarda, antimalarial agents, off-label uses, 238 Porphyrins, photodynamic therapy, 281–282 Posaconazole, 100, 427 indications, oral candidiasis, 669 Postfinasteride syndrome, 377 Postherpetic neuralgia (PHN), 463 Postherpetic neuralgia, corticosteroids, systemic, 141 Postherpetic neuralgia (PHN) treatment aspirin, 363 capsaicin, 647 eutectic lidocaine and prilocaine, 642 Potash, sulfurated, 611t Potassium hydroxide (KOH), 500 Potassium iodide, 446t, 456–457 adverse reactions, 457 pregnancy/lactation risks, 713t contraindications, 457b indications, 456, 457b mechanism of action, 456 monitoring guidelines, 457 off-label uses, 457 pharmacology, 456 Povidone-iodine, 478t, 479

816

Index

Pralatrexate, 407t, 416–417 adverse reactions, 410t indications, 408t Pramoxine, 633t, 644, 645t Pravastatin, 436 dose, 440t drug interactions, 441t pharmacology, 440t structure, 437f–438f Precipitated sulfur, 508, 611, 611t formulations, 505t pregnancy/lactation risks, 721t Predictive testing, cytochrome P-450 polymorphisms, 682 Prednisolone, pediatric dosing, 769t Prednisone osteonecrosis, 16 timing of risk, 16 pediatric dosing, 769t Pregabalin, 462–463 adverse reactions, 463 off-label uses, 463 pharmacology, 448t Pregnancy risks, 711, 712t chemical peels, 596 corticosteroids, 520 drugs, 714 acetaminophen, 716t acyclovir, 494, 495t adapalene, 718t albendazole, 509 amoxicillin, 717t analgesics, 716t anthralin, 629 antiacne agents, 718t antibacterial agents, 717t antifungal agents, 491 aspirin, 716t azalides, 717t azithromycin, 717t bacitracin, 718t β-blockers, 362b bisphosphonates, 433 cefdinir, 717t cephalexin, 717t cephalosporins, 717t chloroprocaine, 717t ciprofloxacin, 717t clindamycin, 96, 717t dicloxacillin, 717t doxycycline, 717t dutasteride, 379 erythromycin, 717t fibric acid derivatives, 441–442 fluoroquinolones, 82, 717t H1 antihistamines, 355 hydrocodone, 717t infliximab, 294 injectable local anesthetics, 641 levofloxacin, 717t lidocaine, 717t lincosamides, 717t

Pregnancy risks (Continued) local anesthetics, 717t macrolides, 79, 717t malathion, 507 mepivacaine, 717t metronidazole, 717t minocycline, 717t minoxidil, 628 mupirocin, 718t neomycin, 718t oxycodone, 716t penicillin G, 717t permethrin, 506 photodynamic therapy contraindications, 285 procaine, 717t pyrethrins, 506 rifamycins, 92 rituximab, 336 salicylic acid, 714 silver sulfadiazine, 714 sodium sulfacetamide, 714 spinosad, 508 statins, 437 tazarotene, 714 tetracaine, 717t tetracyclines, 89 thalidomide monitoring, 462 treatment, spironolactone, 373 tretinoin, 714 trimethoprim, 717t trimethoprim-sulfamethoxazole, 94–95 see also Lactation risks first trimester, 711–712, 712t information sources, 711 low-risk drugs, 714t–715t pre-conception, 711 second trimester, 712–714 shampoos, 582 third trimester, 714 time relation, 711 Premature epiphyseal closure, systemic retinoid adverse reactions, 257 Prescription Drug User Free Act (1992), 51 Prescriptions compounding, 764 informed consent, 754 shampoos, 580 Preservatives, 764 corticosteroid vehicle, 522 Prevention, drug safety. see Drug safety Previtamin D3 (9,10-secosterol precholecalciferol), 557–558 Prilocaine, pregnancy/lactation risks, 717t Primaquine, hematologic toxicity, 696 Primary cutaneous B-cell lymphoma, rituximab treatment, 331 Primary psychiatric disorders, 383 Procaine injectable, 633t pharmacology, 635t pregnancy/lactation risks, 717t

Prodrugs, 8t definition, 3t metabolism, 8, 8t Progestin(s), 373–375 indications, 375 Programmed cell death protein (PD-1) inhibitors, 417–418 Progression step, carcinogenesis, 703 Progressive multifocal leukoencephalopathy (PML) drug withdrawals, 65t Progressive multifocal leukoencephalopathy, rituximab, 336 Proliferative disorders, methotrexate, 161 Proliferative phase, wound healing, 598 Promotion step, carcinogenesis, 703 Propantheline see also Anticholinergic drugs Propionibacterium acnes infection acne vulgaris development, 536–537 photodynamic therapy, 282 see also Acne vulgaris Propranolol, 362 flushing therapy, 362 pediatric dosing, 769t Propylene glycol, 762t hand contact dermatitis, 618 Propylene glycol–induced irritancy, 491, 491t Prostacyclin, 359 Prostaglandin E2 (PGE2), 359 Prostaglandin I2 (PGI2), 359 Prostate cancer, drug-induced dutasteride, 379 finasteride, 377 Protease inhibitors, drug interactions, 737t Protein binding bioavailability, 4 distribution, 728 distribution effects, 3–4 Protime, liver function tests, 687t Provitamin D3 (7-dehydrocholesterol), 558 Prurigo nodularis, 562 Prurigo nodularis treatment thalidomide, 460 vitamin D3, 562 Pruritic dermatoses, PUVA therapy, 265b Pruritus definition, 409t–412t, 413 salicylic acid treatment, 609–610 treatment narrowband UVB phototherapy, 267 nonsteroidal anti-inflammatory drugs, 454–455 Pseudomonas aeruginosa, 468 Pseudotumor cerebri (PTC) (idiopathic intracranial hypertension) systemic retinoid adverse reactions, 257 tetracyclines, 87–88 Psoralen and ultraviolet A (PUVA) therapy, 776 with topical vitamin D3, 562 Psoralen medication and ultraviolet A (UVA). see PUVA

Index

Psoralen plus ultraviolet A (PUVA) photochemotherapy, 264–267 adverse reactions, 266, 266b contraindications, 265, 265b definition, 264 drug interactions, 266 historical aspects, 264 indications, 264–265, 265b cutaneous T-cell lymphoma, 265 dermatitis, 265 mechanism of action, 264 off-label use, 265 papulosquamous dermatoses, 265 photosensitivity dermatoses, 264 psoriasis, 264–265 vitiligo, 265, 267 monitoring, 266 pharmacology, 264, 265b procedure, 265–267 clearance schedule, 265–266 combination treatments, 266, 266b maintenance schedule, 266, 266b methoxsalen administration, 265 UVA radiation, 265, 266b protection, 266 therapeutic guidelines, 264 Psoralens, 264b absorption, 264 bioavailability, 264 definition, 264 excretion, 264 formulations, 264b metabolism, 264 photochemistry, 264 structure, 264, 264f see also PUVA Psoriasis, 583 brazikizumab, 328 definition, 302 interleukin 23 inhibitors, 328 malignancy induction, 705 methotrexate, 160–161, 161b pathogenesis, 287–288, 288f, 302–303, 304t, 305, 311 cells involved, 287 cytokines, 287–288, 288f, 302–303 plaque-type. see Plaque-type psoriasis scalp. see Scalp psoriasis treatment adalimumab, 295 antiangiogenesis agents, 365 bevacizumab, 365 calcitriol, 562 corticosteroids, 517–518 etanercept, 290–291 infliximab, 293 narrowband UVB phototherapy, 267 pimecrolimus, 555 PUVA, 264–265 salicylic acid, 609 tacrolimus, 552 tar, 613

Psoriatic arthritis antimalarial agents, off-label uses, 239 ixekizumab, 317 secukinumab, 315 treatment infliximab, 294 Psychiatric disorders doxepin adverse reactions, 384 drug adherence, 36 primary, 383 secondary, 383 Psychodermatologic disorders, 383–384 classification, 383 management, 383–384 Psychophysiologic disorders, 383, 383t see also specific diseases/disorders Psychoses, 393–394 Psychotropic agents, 90t dermatologic conditions, 395 nonpsychiatric disorders, 384 see also specific drugs PTC. see Pseudotumor cerebri (PTC) (idiopathic intracranial hypertension) Puberty, androgens, 367 Public health crises, 54–60 Public needs, informed consent exceptions, 756 Punch biopsies, eutectic lidocaine and prilocaine, 642 Purple cone flower (Echinacea angustifolia), drug interactions, 739t Pustular psoriasis, calcipotriene treatment, 561 PUVA adverse reactions malignancy induction, 707 melanoma induction, 15 cataracts, 16 management, 19 indications squamous cell carcinoma prevention, 16 public health crises, 55 risk factors, 15 with topical corticosteroids, 517–518 see also Narrowband UVB phototherapy; Psoralens Pygeum (Pygeum africanum), 381 Pyoderma gangrenosum cyclosporine, 192 treatment corticosteroids, 518 etanercept, 297 tacrolimus, 552 ulcers, 600 Pyoderma granulosum, 600 Pyrethrins, 504–506 adverse reactions, 506 formulations, 505t indications, 506 lactation, 506 pharmacology, 504–506 pregnancy, 506

817

Q Quadrivalent human papillomavirus vaccine, 498–499 Quality of life (QoL), interleukin-12/23 inhibitors, 308–309 Quetiapine, 394 Quinacrine, hematologic toxicity, 696 Quinidine, thrombocytopenia, drug-induced, 692t

R RAD (recurrent aphthous stomatitis), 670–671 Radiesse, 651 ‘Radiotherapy Mixture,’ mucositis treatment, 672 Randomized controlled trials (RCTs), 51, 55–56 adverse drug reactions, 56 patient selection, 55 population size, 55 short term, 55 single drug evaluation, 55–56 Ranitidine pediatric dosing, 769t thrombocytopenia, drug-induced, 692t RARE (retinoic acid response element), 249 RARs. see Retinoic acid receptors (RARs) Rashes maculopapular, 409t–410t, 416 papulopustular. see Papulopustular rash ras oncogenes, 703 Ravuconazole, 100 Raynaud’s phenomenon treatment calcium channel blockers, 359 diltiazem, 359 iloprost, 365 nifedipine, 359 pentoxifylline, 364 RBP (retinol-binding protein), 532 RCTs. see Randomized controlled trials (RCTs) Reactive intermediates, hepatotoxicity, 680 Rebound syndrome, corticosteroid adverse reactions, 520 Receptors agonists, 5t antagonists, 5t definition, 5t drugs. see Drug receptors Rechallenge. see Drug rechallenge Recurrent aphthous stomatitis (RAS), 670–671 Red man syndrome, vancomycin, 78 Reesterification (reverse metabolism), acitretin, 248 Referral criteria, hepatotoxicity diagnosis, 685 Refractoriness, 5t Regional nerve block, injectable local anesthetics, 637 Registries, drug safety, 58

818

Index

Remodeling phase, wound healing, 598 REMS. see Risk Evaluation and Mitigation Strategy (REMS) Renal function tests, 14 Renal system, pharmacokinetics, 8 Reproductive system adverse reactions, dutasteride, 379 Reproductive Toxicology Service, 712t Reservoirs, distribution effects, 3–4 Resonant acoustic mixer (RAM), 765 Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, 422–423 Restriction fragment length polymorphisms (RFLPs), thiopurine methyltransferase testing, 28 Retapamulin adverse effects, 471 bacterial coverage, 467t dermatologic uses, 471 mechanism of action, 467t microbiologic activity, 471 pharmacology, 470–471 pregnancy categories, 468t pregnancy/lactation risks, 718t for wound care and minor topical antibacterial infections, 467t Retinal damage, 247 Retinoic acid, 247 Retinoic acid receptors (RARs), 248–249 all-trans retinoic acid/retinol, 536 Retinoic acid response element (RARE), 249 Retinoid(s), 80t, 90t enzyme inhibition, 6t receptor interactions, 5t signal transduction, 7 Retinoid-induced hyperlipidemia, 435–436 Retinoid receptors, adapalene, 534 Retinoids, systemic, 245–260, 246t absorption, 248 adverse reactions, 252–258 bone, 256–257 central nervous system, 257 depression, 256 hair, 257 hematological system, 257–258 hematologic toxicity, 697 hepatic system, 257 inflammatory bowel disease, 256 lipid effects, 255–256 mucocutaneous effects, 255 muscle, 257 nails, 257 ocular system, 257 teratogenicity, 252–254 thyroid gland, 257 contraindications, 253b definition, 245 distribution, 248 drug interactions, 258, 258t excretion, 248 first-generation, 247 half-lives, 248

Retinoids, systemic (Continued) historical perspective, 245–247 indications, 249–260, 249b acne vulgaris, 250–251 with biologic agent, 250 chronic hand eczema, 252 cutaneous T-cell lymphoma, 251 Darier’s disease, 251 dissecting cellulitis of the scalp, 251 generalized pustular psoriasis, 250 hydradenitis suppurativa, 251 ichthyosiform dermatoses, 251 lichen planus, 252 lupus erythematosus, 252 malignancy prevention, 251–252 mycosis fungoides, 251 off-label use, 251–252 pityriasis rubra pilaris, 251 practical considerations, 249 psoriasis, 250 rosacea, 251 Sézary syndrome, 251 mechanism of action, 248–249 ligand-receptor binding, 248–249, 249t metabolism, 248 monitoring, 258, 259b pharmacology, 247–249, 247t physiology, 247f pregnancy guidelines, 254b second-generation, 247 structure, 247–248 therapeutic guidelines, 258–260, 260b third-generation, 247–248 transport, 248 see also specific drugs Retinoids, topical, 529, 529t abbreviations, 533t adverse reactions, 535t, 539–540 cosmeceuticals, 539 definitions, 533t delivery in skin, 532f historical aspects, 529 indications, 535t, 536–539 acne vulgaris, 536–537 actinic keratoses, 537 AIDS-related Kaposi’s sarcoma, 538–539 cutaneous T-cell lymphoma, 538 dermatoses, 539 dysplastic nevi, 538 keloids, 539 lichen planus, 539 oral leukoplakia, 539 photoaging, 537–538 pigmentary disorders, 538 plaque psoriasis, 538 striae distensae, 539 wound healing, 539 mechanism of action, 529, 530t–531t nuclear receptor binding, 533t pharmacology, 529–536 precautions, 535t structure, 529

Retinoids, topical (Continued) teratogenicity, 529–532 see also specific agents Retinoid X receptors (RXRs), 248–249 Retinol-binding protein (RBP), 532 Retinopathy, 239–240 Retinopathy, drug-induced, antimalarial drugs, 15 Retinyl acetate, with polyhydroxy acids, 589–590 REVEAL, adalimumab, 295 Reverse metabolism (re-esterification), acitretin, 248 RFLPs (restriction fragment length polymorphisms), thiopurine methyltransferase testing, 28 RG7204. see Vemurafenib (PLX 4032/ RG7204/RO5185426) Rhabdomyolysis statin adverse reactions, 437–439 statin drug interactions, 439 Rheumatoid arthritis, malignancy induction, 705 Rhinoscleroma, rifamycin treatment, 91 Rhytides. see Facial rhytides treatment Ribosomal protection, tetracyclineresistance, 84 Rickets, 557 Rickettsial disease, tetracyclines, 86 Rifabutin, 91 Rifampin, 89–93 adverse reactions contraceptive failure, 711, 712t hepatotoxicity, 681t, 686t thrombocytopenia, drug-induced, 692t antimicrobial activity, 89–91 drug interactions pimozide, 740 Rifamycins, 80t, 89–93, 93t adverse reactions, 91–92 antimicrobial activity, 89–91 dosage, 93 drug interactions, 92–93 indications, 91 lactation, 92 pharmacokinetics, 91 pregnancy, 92 see also specific drugs Rifapentine, 91 Ring block, injectable local anesthetics, 637 Risankizumab adverse effects, 327–328 clinical trials, 327t efficacy, 326–327 pharmacokinetics, 326 pharmacology, 326–328 Risedronate, 431 metabolism, 431 osteoporosis therapy, 432–433 pregnancy, 433 structure, 431f therapeutic guidelines, 434

Index

Risk Evaluation and Mitigation Strategy (REMS) drug withdrawal, 63 labeling, 63 Risk factors, drug safety, 15–16 Risk-risk assessment, 13 Risperidone, 393 Rituximab, 400–401 administration, 331, 331b, 333–334 adverse events, 335 adverse reactions hematologic toxicity, 697 antiautoimmune response durability, 333 B-cell depletion, 335 biosimilars, 337 combination therapy, 331 contraindications, 331, 331b immunomodulatory medications, 337, 337b indications, 331, 331b bullous pemphigoid, 331b, 334–335 cutaneous lupus erythematosus, 331b, 335 dermatomyosititis, 331b, 335 epidermolysis bullosa Acquisita, 331b, 335 graft-versus-host disease, 331b, 335 mucous membrane pemphigoid, 331b, 335 paraneoplastic pemphigus, 331, 331b pemphigus foliaceus, 331, 331b, 334 pemphigus vulgaris, 331b, 333–334 primary cutaneous B-cell lymphoma, 331 vasculitis, 331, 335 mechanism of action, 331–333, 333f monitoring guidelines, 337, 337b on new immunity formation, 332 off-label use, 334–335 on pathogenic autoimmunity, 332–333 pharmacokinetics, 331 pharmacology, 331–333 precautions, 335 on preexisting immunity, 332 pregnancy/lactation risks, 722t–723t second generation anti-CD20 agents, 337 severe mucocutaneous reactions, 335–336 special populations, 336 structure, 331, 332f, 332t warnings, 335 RO5185426. see Vemurafenib (PLX 4032/ RG7204/RO5185426) Rofecoxib, withdrawal, 65t Romidepsin, 407t, 415 adverse reactions, 410t indications, 408t Rosacea treatment á-hydroxy acids, 588 azelaic acid, 473t, 477 benzoyl peroxide, 473t, 474 clindamycin, 473t dapsone, 473t

Rosacea treatment (Continued) erythromycin, 473t metronidazole, 473t, 476–477 pimecrolimus, 555 sodium sulfacetamide, 473t sulfur, 612 systemic retinoids, 251 tacrolimus, 552 tetracyclines, 85–86 Rosuvastatin, 436 dose, 440t drug interactions, 441t, 739 FDA advice, 439 pharmacology, 440t structure, 437f–438f Routes of administration, absorption effects, 2 Ruxolitinib, 207 RXRs (retinoid X receptors), 248–249

S Safety. see Drug safety Salicylic acid (SA), 495t, 502, 608–611 adverse reactions, 610–611 chemical peels, 593 chemistry, 608 indications acne, 609 actinic keratoses, 610 calluses, 608–609 chemical peels, 609 dermatophyte infections, 609 hyperhidrosis, 610 hyperkeratosis, 610 ichthyosis, 609 molluscum, 608–609 pain, 609–610 pruritus, 609–610 psoriasis, 609 scalp psoriasis, 609 seborrheic dermatitis, 609 sunscreens, 609 verruca, 608–609 keratolytic shampoos, 577t mechanism of action, 608 pharmacology, 608 pregnancy/lactation risks, 718t shampoo, 578 structure, 608f systemic absorption, 579 with topical corticosteroids, 518 Salicylism, 610–611, 610b Sandimmune. see Cyclosporine SANDS trial, 443 Saw palmetto (Serenoa repens), 381 Scabies, treatment antiparasitic agents, 504 permethrin, 506 sulfur, 612 Scalp, contact dermatitis, 618–619 Scalp psoriasis salicylic acid, 609 treatment

819

Scalp psoriasis (Continued) calcipotriene, 561 calcipotriene/topical betamethasone dipropionate, 561 calcitriol, 562 corticosteroids, 517 Scars/scarring, chemical peel adverse reactions, 596 SCC. see Squamous cell carcinoma (SCC) Schamberg’s disease, tetracycline effects, 89 Scleroderma localized, tacrolimus treatment, 552 treatment extracorporeal photochemotherapy, 277 intravenous immunoglobulin, 400 UVA-1 phototherapy, 269–270 Scleromyxedema, 400 corticosteroids, 400 intravenous immunoglobulin, 400 Sculptra, 651–653 SEAS, ezetimibe, 443 Seborrheic dermatitis metronidazole, 477 pathogenesis, 583 treatment corticosteroids, 518 pimecrolimus, 555 salicylic acid, 609 shampoos, 583 tacrolimus, 552 tar, 613 Sebum, acne vulgaris development, 536–537 Secondary infections, tetracycline effects, 88 Secondary psychiatric disorders, 383 Second-generation penicillins, 73 Second-generation systemic retinoids, 247 Second messengers definition, 5t pharmacodynamics, 7 9,10-Secosterol precholecalciferol (previtamin D3), 558 Secukinumab dermatologic indications, 313 dosage, 313 efficacy outcomes, 315t off-label uses, 315 pharmacology, 314 plaque psoriasis, 314–315 pregnancy/lactation risks, 723t psoriatic arthritis, 315 safety and monitoring guidelines, 315–316 Secukinumab (AIN-457), 308–309 Secular trend studies, 59t Sedation/sedatives doxepin adverse reactions, 386 first-generation antihistamines, 351–352 thalidomide interactions, 461t SEER database, malignancy induction, 702 Selective β-blockers, 772 Selective serotonin reuptake inhibitors (SSRIs), 387–388, 388t–389t, 390b adverse reactions, 388

820

Index

Scalp psoriasis (Continued) choice of, 390–391, 395 indications, 387–388, 391t receptor interactions, 5t see also specific drugs Selenium sulfide, 482t, 488, 577t antiproliferative effects, 578 corticosteroids, 578 pregnancy/lactation risks, 724t selenium sulfide, 578 shampoos, 579 systemic absorption, 579 Self-reporting, adherence measures, 34 Sensitive skin, sunscreens, 573 Serotonin syndrome, doxepin, 388 Serotonin syndrome, linezolid, 96 Sertaconazole, 482t adverse effects, 485 indications, 485 pharmacology, 485 Sertraline, 387–388, 388t–389t Serum sickness-like reactions (SSLR), tetracycline effects, 88 Severe hyperglycemia, 143 Severe myopathy, finasteride adverse reactions, 377 Sexual and Psychiatric Functioning and ‘Postfinasteride Syndrome, 377 Sexual function effects finasteride adverse reactions, 377 selective serotonin reuptake inhibitors adverse reactions, 388 venlafaxine adverse reactions, 390 Sexually transmitted diseases, tetracyclines, 73 Sézary syndrome, systemic retinoid treatment, 251 Shampoos, 577t adjunctive therapy, 581 adverse reactions, 581–582 anti-inflammatory, 577t antimicrobial, 577t application technique and frequency, 582–583 chronic use, 583 contraindications, 581 cytostatic, 577t drug interactions, 584 historical perspective, 578 hypoallergenic, 577t indications, 580b seborrheic dermatitis, 576–578 tinea capitis, 584 keratolytic, 577t, 578 mechanism of action, 578–579 pharmacology, 578–579 pregnancy, 582 rotational therapy, 582–583 surfactants, 578 therapeutic guidelines, 582–584 wetting agents, 578 Short-term-randomized controlled trials, 55 Side effects. see Adverse drug reactions (ADRs)

Signal generation, 58 adverse drug reactions, 58 Signaling induced cell death, rituximab, 332 Signal transduction definition, 5t pharmacodynamics, 6–7 retinoids, 7 rituximab inhibition, 332 Signed consent forms, 755–756 Sildenafil (Viagra), 364 Silicone fillers, 653 Silikon, 652t Silver sulfadiazine, 471–472 bacterial coverage, 467t mechanism of action, 467t patch testing, 468t pregnancy categories, 468t pregnancy/lactation risks, 718t for wound care and minor topical antibacterial infections, 467t Silymarin, 625t Simvastatin, 436 dose, 440t drug interactions, 441t, 739 FDA restrictions, 438–439 pharmacology, 440t structure, 437f–438f Sinecathechin, topical, 502–503 Sirolimus, erosive gingivostomatitis treatment, 667 Skin cleansers see also specific types dry, 411t–412t hydration, 9t percutaneous absorption, 9t pigmenting products see also Dihydroxyacetone (DHA) sensitive, sunscreens, 573 surgery, eutectic lidocaine and prilocaine, 641–642 see also specific anatomical features Skin and subcutaneous tissue disorders, 425t Skin-cancer, niacinamide treatment, 453 SLE. see Systemic lupus erythematosus (SLE) Slow acetylators, pharmacogenetics, 7 SNARE, nerve conduction, 657 Soap(s) see also specific types Social history, chronic wound care, 598 Sodium lauryl sulfate, recurrent aphthous stomatitis, 670 Sodium sulfacetamide, 478 acne vulgaris, 473t pregnancy categories, 474t pregnancy/lactation risks, 718t rosacea, 473t Solar Urticaria, UVA-1 phototherapy, 270 Solvents, corticosteroid vehicle, 514 Sonidegib, 420, 421f, 425t, 425b see also Hedgehog (Hh) pathway

Sorafenib, 407t, 409–413 indications, 408t Soriatane. see Acitretin Sotret. see Isotretinoin Spearmint herbal tea (Mentha spicata labiatae), 381 Special populations adherence, 38–39 rituximab, 336 SPF level, sunscreens, 571 Spinosad, 508 formulations, 508t lactation, 508 pregnancy, 508 pregnancy/lactation risks, 721t Spirochete infections, tetracyclines, 86 Spironolactone, 369–371 adverse effects, 372–373 adverse reactions agranulocytosis, 691t pregnancy/lactation risks, 713t doses, 371–373 drug interactions, 373 indications, 371, 371b monitoring guidelines, 373 off-label uses, 371 pharmacology, 369–371, 369t, 370f receptor interactions, 5t structure, 371, 371f Spontaneous report programs, drug safety, 58 Sporotrichosis, potassium iodide treatment, 457 Sprays, sunscreens, 571 Squalene epoxidase, drug inhibition, 6t Squamous cell carcinoma (SCC) etiology drug-induced, 708t organ transplantation, 707 PUVA, 266, 707 tar, 613–614 viral infections, 704, 704t prevention drug-induced, 708t PUVA therapy, 16 systemic retinoids, 251–252 treatment epidermal growth factor receptor inhibitors, 406 photodynamic therapy, 284 SSLR. see Serum sickness-like reactions (SSLR) SSRIs. see Selective serotonin reuptake inhibitors (SSRIs) Standards of care, drug safety, 13 Stanozolol see also Attenuated androgens. Staphylococcal colonization, mupirocin, 470 Staphylococcus aureus infection, bacitracin treatment, 466 Stasis dermatitis, 622 Static Physician Global Assessment (sPGA) scores, 326–327

Index

Statins, 80t, 436–439 absorption, 436 adverse reactions, 437–439 rhabdomyolysis, 437–438 bioavailability, 436 contraindications, 437 doses, 440t drug interactions, 441t, 737t, 739 rhabdomyolysis, 439 rifamycins, 93t excretion, 436–437 indications, 437 mechanism of action, 437 metabolism, 436–437 monitoring guidelines, 439 pharmacology, 436–437, 440t pregnancy, 437 structure, 436, 437f–438f therapeutic guidelines, 439 withdrawal, 66 see also specific drugs Statistics adverse drug effects, 56, 56t drug safety, 56t Steady state, 3t Steatosis, microvesicular, 685t Steatosis progressing to fibrosis, hepatotoxicity, 682b Steroids. see Corticosteroid(s) Stevens-Johnson Syndrome chronic idiopathic urticaria, 192 Corticosteroids, systemic, 140 Stevens-Johnson syndrome, 88 Sticks, sunscreens, 572 Stiffening agents, 762 Stiffness, pimozide adverse reactions, 392–393 Stinging nettle (Urtica diocia), 381 St John’s wort, drug interactions, 739t Stomafate suspension, mucositis treatment, 672 Stomatitis. see Mucositis (stomatitis) Stoughton Vasoconstrictor Assay, 52 corticosteroids, 512 Stratum corneum distribution effects, 3–4 percutaneous absorption, 9, 9t Striae distensae, retinoid treatment, 539 Study design, drug safety, 56t Subcutaneous fillers. see Dermal fillers Subcutaneous nodules, dermal filler adverse reactions, 654 Subepidermal blister formation, 400 Sublimed sulfur, 611, 611t Sucralfate suspension mucositis treatment, 672 recurrent aphthous stomatitis treatment, 670 Sulbactam-amoxicillin, 77 Sulconazole, 482t adverse effects, 485 indications, 485 pharmacology, 484–485 pregnancy/lactation risks, 719t

Sulfamethoxazole pregnancy/lactation risks, 717t trimethoprim combination. see Trimethoprim-sulfamethoxazole (TMP-SMX) Sulfapyridine, linear IgA bullous dermatosis treatment, 401 Sulfasalazine, adverse reactions agranulocytosis, 691t hematologic toxicity, 695–696 thrombocytopenia, 695–696 Sulfonamides adverse reactions contraceptive failure, 714 hematologic toxicity, 690 hepatotoxicity, 686t drug interactions, methotrexate, 741 enzyme inhibition, 6t metabolism, glucose-6-phosphate dehydrogenase, 30t Sulfones, 80t drug interactions, rifamycins, 93t metabolism, 30t Sulfotransferases, polymorphisms, 680t Sulfur, 611–612 adverse reactions, 612 chemistry, 611 mechanism of action, 611–612 mechanisms of action, 611–612 pharmacokinetic, 612 pharmacology, 611–612 types, 613t see also specific types Sulfurated lime, 611, 611t Sulfurated potash, 611, 611t Sulisobenzone, sunscreens, 567t Sunless tanners, 574–575 Sunscreens, 565–575 active ingredients, 566, 567t see also specific ingredients adverse reactions, 572, 572b application, 574 commercially available, 574t contraindications, 570b indications, 569–570, 570b labeling definitions, 566t pending approval, 570t photoprotection instructions, 572–573, 573b physical blockers, 566 preventative strategy, 565–566 PUVA, 266 regulation, 565–566 salicylic acid, 609 special patient groups, 573 SPF level, 571 titanium dioxide, 567t UVA blockers, 566b, 567–568 UVB blockers, 566b vehicles, 571–572 vitamin D synthesis, 574 Superficial chemical peels, 592–593, 593t

821

Superficial shave excisions, eutectic lidocaine and prilocaine, 642 Superficial small nonfacial basal cell carcinoma, imiquimod treatment, 498 Surfactants, shampoos, 578 Surgical history, chronic wound care, 598 Surveys, adherence measures, 34–35 Sweet’s syndrome treatment etanercept, 291 nonsteroidal anti-inflammatory drugs, 454 Symptom identification, drug safety, 14 Syphilis, tetracycline treatment, 86 Systemic absorption, photodynamic therapy, 285 Systemic circulation, distribution effects, 3–4 Systemic corticosteroids adverse effects and preventive strategies, 771–772 general principles, 771 paediatric patients, 771–772 tapering systemic corticosteroids, 772 Systemic drug bioequivalence, 52 Systemic drugs informed consent, 755–756 medications vs., 12–13 see also specific drugs Systemic immunosuppressive therapies, 773–776 Systemic lupus erythematosus (SLE), treatment corticosteroids, 402 immunosuppressants, 402 intravenous immunoglobulin, 402 UVA-1 phototherapy, 270 Systemic retinoids acitretin, 773 isotretinoin, 773 Systemic sclerosis (SSc), 423–424 Systemic sclerosis treatment, calcium channel blockers, 359

T Tacalcitol, 560 Tachyphylaxis corticosteroid adverse reactions, 521 definition, 5t H1 antihistamines, 356 percutaneous absorption, 10 Tacrolimus, 549–553 adverse reactions, 552 erosive gingivostomatitis, 667 indications, 550–551 atopic dermatitis, 550 contact dermatitis, 552 cutaneous Crohn’s disease, 552 granuloma faciale, 552 lichen planus, 554–555 lichen sclerosus, 552 localized scleroderma, 552 lupus erythematosus, 552 meta-analysis, 550 morphea, 552

822

Index

Tacrolimus (Continued) psoriasis, 552 pyoderma gangrenosum, 552 rosacea, 552 seborrheic dermatitis, 552 vitiligo, 554–555 lack of efficacy, 552 mechanism of action, 550 enzyme inhibition, 6t off-label use, 551–552 pharmacology, 550 pimecrolimus vs., 551 pregnancy/lactation risks, 721t systemic absorption, 555 atopic dermatitis, 555 Netherton’s syndrome, 555 Tadalafil, 364 Tar, 612–614 adverse reactions, 613–614 antimitotic shampoos, 577t chemistry, 612–613 compounding, 613 mechanism of action, 613 pharmacology, 612–613 systemic absorption, 579 therapeutic guidelines, 583 Tardive dyskinesia, pimozide adverse reactions, 393 Target organs, drug interactions, 14–15 Targretin. see Bexarotene Tavaborole, 482t, 488 pregnancy/lactation risks, 719t Taxanes, 414–415 Tazarotene, 529t, 534–535 adverse reactions teratogenicity, 713t application guidelines, 537 indications, 536t cutaneous T-cell lymphoma, 538 photoaging, 538 plaque psoriasis, 538 inducible genes, 534 mechanism of action, 530t–531t pharmacology, 531t precautions, 535t pregnancy/lactation risks, 718t structure, 530f with topical corticosteroids, 518 TCA. see Trichloroacetic acid (TCA); topical T cell(s) histamine H2 receptors, 350 psoriasis, 288 T-cell receptor binding, 6–7 T-cell activation inhibitors, malignancy induction, 701t, 706 T-cell(s), intravenous immunoglobulin therapy effects T-cell lymphoma, cutaneous. see Cutaneous T-cell lymphoma (CTCL) T-cell-mediated autoimmune dermatoses, 273, 275b, 276–278

T-cell receptor (TCR) signal, 421 T-cell binding, 6–7 Teamwork approach, drug safety, 17 Teenagers, adherence, 35–36 Tegaserod, withdrawal, 65t Tegretol. see Carbamazepine Telogen effluvium, systemic retinoid adverse reactions, 257 TEN. see Toxic epidermal necrosis (TEN) Tendinitis, fluoroquinolones, 81 Tendon rupture, fluoroquinolones, 81 Teratogenicity, 424, 713t finasteride, 377–378 retinoids, 252–254, 253b, 529–532 thalidomide, 460 Teratogen Information Service (TERIS), 712t Terbinafine, 100, 100t, 482t, 486–487 adverse effects, 110–111 adverse reactions hematologic toxicity, 697 contraindications, 108 deep fungal infections, 108 drug interactions, 110t drug risks profile, 109b enzyme inhibition, 6t indications, 104–105 liver cirrhosis, 102 mechanism of action, 103 off-label uses, 108 onychomycosis, 108 pharmacokinetics in hair, 102–103 in nails, 102 in skin, 102–104 pregnancy/lactation risks, 719t structures, 101f tinea capitis, 106 tinea corporis, 106 Terfenadine, withdrawal, 65, 65t TERIS (Teratogen Information Service), 712t Terminal elimination, 3t Tests drug safety, 17 glucose-6-phosphate dehydrogenase polymorphisms, 29–30 Tetracaine, pregnancy/lactation risks, 717t Tetracyclines, 82–89, 90t, 400, 713t adverse reactions, 87–89 acute vestibular side effects, 87 autoimmune hepatotoxicity, 89 benign intracranial hypertension, 87–88 contraceptive failure, 711 drug hypersensitivity syndrome, 88 dyspigmentation, 88 gastrointestinal system, 87 hypersensitivity reactions, 88 lupus-like syndrome, 88–89 photosensitivity, 88 pregnancy/lactation risks, 89 secondary infections, 88 vasculitis, 89

Tetracyclines (Continued) antibacterial activity, 84 anti-inflammatory effects, 82–83 classification, 84 dosages, 89 drug interactions, 89 indications, 85–87 acne vulgaris, 85 atypical mycobacterial infections, 87 granulomatous dermatoses, 86 immunobullous dermatoses, 86 inflammatory dermatoses, 86 ocular rosacea, 85 perioral dermatitis, 85 Rickettsial disease, 86 rosacea, 85–86 sexually transmitted diseases, 87 spirochete infections, 86 syphilis, 86 pharmacokinetics, 84 pharmacology, 84–85 resistance, 84 see also specific drugs Tetraphthalydine dicamphor sulfonic acid (ecamsule), sunscreens, 567t, 568 Thalidomide, 446t, 457–462 absorption, 458 adverse reactions, 460–461 teratogenicity, 713t bioavailability, 458 contraindications, 459–460, 459b drug interactions, 461, 461t excretion, 458 historical aspects, 457–458 indications, 459–462, 459b recurrent aphthous stomatitis, 670 mechanism of action, 449t, 458–459 metabolism, 458 monitoring guidelines, 461–462, 462b off-label uses, 459–460 pharmacology, 448t, 458–459 public health crises, 55 structure, 457–458, 458f Thalomid Remsr program, thalidomide monitoring, 461 T-helper 17 cell(s) (Th17) differentiation, 302–303 psoriasis, 288f, 302–303 Theoretical infection risk, 403 Therapeutic index, 3t Therapeutic privilege, informed consent exceptions, 756 Therapeutic range, 3t Th17 helper T cells, 312 Thiabendazole, 129–130, 131t, 509 adverse effects, 130 dosing, 130t drug interactions, 130 indications, 130 mechanism of action, 130 pharmacology, 129–130 pregnancy, 130

Index

Thiabendazole (Continued) resistance, 130 therapeutic guidelines, 130t Thickening agents, corticosteroid vehicle, 514 Thin-layer rapid use epicutaneous (TRUE) test, corticosteroid allergy, 621 Thioguanine, 28–29, 211–212 Thiopurine methyltransferase (TPMT), 774 drug metabolism, 28–29 drug safety, 15 polymorphisms, 27t, 28–29 epidemiology, 27t, 28–29 testing for, 28–29 Third-generation penicillins, 73 Third-generation systemic retinoids, 247–248 Thresholds of concern, drug safety, 18 Thrombocytopenia, drug-induced, 690 azathioprine, 694 gold, 697 penicillamine, 697 sulfasalazine, 695–696 tetracycline, 89 trimethoprim-sulfamethoxazole, 692 Thromboembolic effects, intravenous immunoglobulin adverse reactions, 403 Thromboembolic events (TE), thalidomide adverse reactions, 460 Thromboxane A2 (TXA2), aspirin, 362–363 Thymidylate synthase phase II drug metabolism, 30–31 polymorphisms, 27t Thyroid gland potassium iodide monitoring, 457 systemic retinoid adverse reactions, 257 Thyroid hormones, rifamycins, 93t Thyroid replacement therapy, 435 see also Bexarotene Ticarcillin-clavulanate, 77 Ticlopidine, agranulocytosis, 691t Ticrynafen, withdrawal, 64t, 678t Tildrakizumab adverse effects, 326 clinical trials, 325t efficacy, 325–326 pharmacokinetics, 324–325 pharmacology, 324–326 pregnancy/lactation risks, 723t Tiludronate, 432t Timing of risk, drug safety, 16 Tinea capitis, 106 dosing, 107t fluconazole, 106 griseofulvin, 106 itraconazole, 106 shampoos, 583–584 terbinafine, 106 Tinea corporis, 106 fluconazole, 106 griseofulvin, 106 itraconazole, 106 terbinafine, 106 Tioconazole, pregnancy/lactation risks, 719t

Tissue reservoirs, 3t Titanium dioxide, sunscreens, 567t, 569 TMP-SMX. see Trimethoprimsulfamethoxazole (TMP-SMX) Tocopherol. see Vitamin E Tofacitinib, pregnancy/lactation risks, 722t–723t Tolerance definition, 5t H1 antihistamines, 356 Top 100 Drug Interactions: A Guide to Patient Management, 726 Topical agents antibacterial. see Antibacterial agents; topical antifungal agents. see Antifungal agents; topical antiparasitic drugs. see Antiparasitic drugs; topical antiviral agents. see Antiviral agents; topical chemotherapeutic agents. see Cytotoxic agents distribution effects, 2 drug approval process, 52 immediate hypersensitivity (Coombs-Gell type I reactions), 10 retinoids. see Retinoids; topical systemic drugs vs., 12 see also specific drugs Topical anesthetics, pediatric patients, 768–769 Topical β-blockers, 772–773 Topical calcineurin inhibitors (TCI), pediatric patients, 770–771 Topical corticosteroids (TCS), pediatric patients, 769–770 Topical phosphodiesterase-4 inhibitor (Crisaborole), 771 Topoisomerase inhibitors, 407t, 414 indications, 408t see also specific drugs Torsades de pointes, drug withdrawals, 65t Toxic effects, injectable local anesthetics, 637–639 Toxic epidermal necrolysis, corticosteroids, systemic, 140 Toxic epidermal necrosis (TEN) corticosteroids, 401 intravenous immunoglobulin, 401–402 Toxicity drug withdrawals, 66 tar adverse reactions, 614 Toxoplasma gondii infections, interleukin-12/23 inhibitors, 310 Transaminase levels drug withdrawals, 66 systemic retinoid adverse reactions, 257 see also specific transaminases Transcription factors corticosteroids, 7 corticosteroids, systemic, 137–139, 138f pharmacodynamics, 6–7

823

Transfusion, hematologic toxicity treatment, 698 Transplants. see Organ transplantation Treatment choice, adherence, 36–37, 37b Treatment complexity, adherence effects, 37 Treatment evaluation, 764–765 Tretinoin, 246 application guidelines, 537 indications acne vulgaris, 529 actinic keratoses, 537 hairy tongue, 670 photoaging, 529 wound healing/keloids, 539 pharmacology, 246t pregnancy/lactation risks, 718t structure, 529, 530f Triamcinolone erosive gingivostomatitis treatment, 667 potency, 513t structure, 513f Triamcinolone acetonide, intralesional, recurrent aphthous stomatitis, 670 Triazolam, antifungal interactions, 737 Triazole, mechanism of action, 103 Triazoles, 108–109 see also specific drugs Trichloroacetic acid (TCA), topical, 501 chemical peel, 594 Triclosan, 478, 478t Tricyclic antidepressants dermatologic conditions, 395 drug interactions epinephrine, 646 Triglycerides (TG), 435 Trimethoprim enzyme inhibition, 6t pregnancy/lactation risks, 717t Trimethoprim-sulfamethoxazole (TMPSMX), 93 adverse reactions agranulocytosis, 691 hematologic toxicity, 696 pancytopenia, 696 pregnancy/lactation risks, 94–95 thrombocytopenia, 692 dosage, 95 drug interactions, 95 pediatric dosing, 769t see also specific drugs Triple response of Lewis, 350–351 Troglitazone, withdrawal, 64t, 65, 678t Trolamine salicylate, sunscreens, 567t Trovafloxacin, withdrawal, 64t TRUE (thin-layer rapid use epicutaneous) test, corticosteroid allergy, 621 Tuberculosis, tumor necrosis factor inhibitor adverse reactions, 292 Tufted angioma, nonsteroidal antiinflammatory drug treatment, 454 Tumescent anesthesia, 637 Tumor lysis syndrome, rituximab, 336

824

Index

Tumor lysis syndrome, rituximab adverse reactions, 336 Tumor necrosis factor-α (TNF-α), 298 Tumor necrosis factor (TNF-α) inhibitors, 289t adverse reactions autoimmunity, 300 children, malignancy, 299 congestive heart failure, 300 hematologic toxicity, 300 infections, 299 lymphoma, 298–299 malignancy induction, 701t neurological disease, 300 skin cancer, 299 boxed warnings for, 15 drug safety, 16 monitoring, 17 monitoring guidelines, 300 opportunistic infections, 15 pediatric patients, 775 see also specific drugs Tween 80, 762t TXA2 (thromboxane A2), aspirin, 362–363

U UDP glucuronyl transferases, polymorphisms, 680t Ulcerated hemangiomas of infancy, becaplermin, 629 Ulcerative gingivostomatitis, acute necrotizing, 671 Ulcers arterial, 601 chronic leg, contact dermatitis, 622 drug-induced bisphosphonates, 433 gastric, 433 percutaneous absorption, 9t venous. see Venous ulcers UltIMMa-1 and -2, risankizumab, 327 Ultraviolet B (UVB), 424 Ultraviolet-induced erythema, nonsteroidal anti-inflammatory drugs, 455 Ultraviolet light. see under UVA United States Pharmacopeia (USP), 760 Urea, 614–615 adverse reactions, 615 indications, 614–615 pregnancy/lactation risks, 724t structure, 608f, 614–615 Urticaria chronic, antihistamines, 356–357 chronic autoimmune. see Chronic autoimmune urticaria contact, sunscreen adverse reactions, 572 treatment cetirizine, 354 histamine, 350 nonsteroidal anti-inflammatory drugs, 455

Urticarial vasculitis, nonsteroidal anti-inflammatory drugs, 455 Ustekinumab, 303, 303t–304t, 303f, 305–310 adverse effects, 309 clinical trials, 307t, 309 drug risk profile, 309b efficacy, 308–309 indications, 304t pharmacokinetics, 305–308 pharmacology, 305–308 pregnancy/lactation risks, 723t UVA, definition, 566, 566t UVA-1 phototherapy, 265, 266b indications, 269–270, 269b UVA protection, sunscreens, 571, 571t UVB definition, 566t with topical vitamin D3, 562

V Valacyclovir adverse effects, 121 adverse reactions enzyme inhibition, 6t drug interactions, 121 indications, 118b, 119–120 Herpes Zoster, 120 off-label uses, 120–121 pharmacology, 117t pregnancy/lactation risks, 721t risks, 118b Valdecoxib, withdrawal, 64, 65t Vancomycin, 77–78 adverse reactions hematologic toxicity, 697 thrombocytopenia, drug-induced, 692t Vardenafil, 364 Varicella-Zoster virus vaccines, 122–123 Vascular malformations, nonsteroidal anti-inflammatory drug treatment, 454 Vascular proliferations, hepatotoxicity, 685t Vasculature pathophysiology, 359 thalidomide, 458–459 Vasculitis azathioprine, 173 methotrexate, 162 tetracycline effects, 89 treatment adalimumab, 296 colchicine, 451 etanercept, 292 infliximab, 294 rituximab, 331, 335 Vasoactive agents, 359–365 see also specific drugs Vehicles adherence effects, 37 α-hydroxy acids formulations, 589 percutaneous absorption, 9t–10t, 10

Vemurafenib (PLX 4032/RG7204/ RO5185426), 407t, 418 adverse reactions, 409t indications, 408t Venlafaxine, 386t, 390 Veno-occlusive hepatotoxicity, 685t Venous insufficiency with ulcers, pentoxifylline treatment, 364 Venous ulcers, 598 dressings see also specific dressings physical examination, 601 Verapamil grapefruit juice interactions, 738–739 keloid therapy, 360–361 Verruca vulgaris, treatment bleomycin, 499–500 cantharidin, 501–502 cidofovir, 496–497 5- fluorouracil, 502 intralesional immunotherapy, 499 quadrivalent human papillomavirus vaccine, 498 salicylic acid, 608–609 Vertex scalp, 376 Vesiculobullous dermatoses, thalidomide, 460 Viagra (sildenafil), 364 Viral hepatitis, hepatotoxicity vs., 685 Viral infections, malignancy induction, 704, 704t see also specific viruses Vismodegib, 420, 420f, 423, 425t, 425b see also Hedgehog (Hh) pathway Visual Acuity Score (VAS), 293–294 Vitamin A dietary form, 247 historical perspective, 245 physiology, 247 see also other retinoids Vitamin C, 624–626 Vitamin C, topical, 624–626 indications, 624–626 plant-derived, 625t Vitamin D3 biosynthesis, 558 metabolism, 558 structure, 560f Vitamin D3, topical, 558 adverse reactions, 563 allergic contact dermatitis, 563 hypercalcemia, 563 irritation, 563 photosensitivity, 563 analogs, 560 combination therapies, 562 with PUVA, 562 with systemic treatments, 562 with topical corticosteroids, 562 ultraviolet B and psoralen plus ultraviolet A, 562 with UVB, 562 historical aspects, 557–558

Index

indications, 444, 444b keratinization disorders, 562 morphea, 562 prurigo nodularis, 562 vitiligo, 562 mechanism of action, 559 off-label uses, 562–563 pharmacology, 558–559 rickets, 557 structure, 558 with topical corticosteroids, 517 see also specific agents Vitamin E, 446t, 462 topical, 626 Vitamin K (phytonadione), 627 Vitiligo pimecrolimus vs., 551–552 tacrolimus, 551–552 treatment corticosteroids, 519 narrowband UVB phototherapy, 269 pimecrolimus, 554–555 PUVA, 265, 267 vitamin D3, 562 Voluntary reporting systems, malignancy induction drug assessment, 703 Voriconazole, 100 adverse effects, 111 drug interactions, 739 pregnancy/lactation risks, 719t systemic oral candidiasis, 669 Vorinostat, 407t, 415 adverse reactions, 410t indications, 408t

W WAPs (written action plans), adherence effects, 38 Warfarin, drug interactions, 740 Warnings and Precautions labeling, 63

Warts anogenital, 499, 501, 503 genital. see Condylomata acuminata (genital warts) treatment nongenital, 501 perianal, 498 Wart treatment imiquimod, 498 trichloroacetic acid (TCA), 501 Water-in-oil emulsions, 763t Water-repellents, 763 Water soluble agents, 763t Wegener granulomatosis, 399 Well’s syndrome, corticosteroid treatment, 518 Wetting agents, shampoos, 578 White coat compliance, adherence effects, 38 WHO (World Health Organization), pregnancy/ lactation risks information, 712t Wingless/integrated (Wnt) signal transduction pathways, 424 Withdrawal dyskinesia, pimozide adverse reactions, 393 Withdrawals of drugs. see Drug withdrawals; specific drugs Wolff-Chaikoff effect, potassium iodide monitoring, 457 Wood tar, 613 World Health Organization (WHO), pregnancy/ lactation risks information, 712t Wound(s), factitial, 600 Wound healing chronic wounds. see Chronic wound care coagulation, 598 ideal environment, 598 inflammatory phase, 598 physiology, 598 proliferative phase, 598 remodeling phase, 598

825

Wound healing (Continued) treatment β-blockers, 362 calcium channel blockers, 360 retinoids, 539 Wound history, chronic wound care, 598 Written action plans (WAPs), adherence effects, 38

X Xanthine bronchodilators, 90t, 93t Xanthine oxidase, azathioprine metabolism, 693–694 Xerosis epidermal growth factor receptor inhibitors adverse reactions, 406–409 treatment α-hydroxy acids, 587 urea, 614–615 Xerostomia (dry mouth), 673–674, 673t as adverse reactions, 673t over-the-counter medication, 674t XVII collagen, 400

Z Zemaphyte interactions, 739t Zinc oxide, sunscreens, 567t, 569 Zinc pyrithione cytostatic shampoos, 577t shampoos, 579, 583 systemic absorption, 579 Zinc sulfate, 446t, 462–463 Zinc, topical, 626 Zoledronate, 431, 432t administration, 431 excretion, 431 metabolism, 431 Zomepirac withdrawal, 678t Zyderm I, 650 Zyderm II, 651